The present invention relates generally to a novel class of pyrrolopyrazinones which are useful as serine protease inhibitors, and more particularly as Hepatitis C virus NS3 protease inhibitors. This invention also relates to pharmaceutical compositions comprising these compounds and methods of using the same.
Hepatitis C virus (HCV) is the major cause of transfusion and community-acquired non-A, non-B hepatitis worldwide. Approximately 2% of the world""s population are infected with the virus. In the Unites States, hepatitis C represents approximately 20% of cases of acute hepatitis. Unfortunately, self-limited hepatitis is not the most common course of acute HCV infection. In the majority of patients, symptoms of acute hepatitis resolve, but alanine aminotransferase (a liver enzyme diagnostic for liver damage) levels often remain elevated and HCV RNA persists. Indeed, a propensity to chroninicity is the most distinguishing characteristic of hepatitis C, occurring in at least 85% of patients with acute HCV infection. The factors that lead to chronicity in hepatitis C are not well defined. Chronic HCV infection is associated with increased incidence of liver cirrhosis and liver cancer. No vaccines are available for this virus, and current treatment is restricted to the use of alpha interferon, which is effective in only 15-20% of patients. Recent clinical studies have shown that combination therapy of alpha interferon and ribavirin leads to sustained efficacy in 40% of patients (Poynard, T. et al. Lancet 1998, 352, 1426-1432.). However, a majority of patients still either fail to respond or relapse after completion of therapy. Thus, there is a clear need to develop more effective therapeutics for treatment of HCV-associated hepatitis.
HCV is a positive-stranded RNA virus. Based on comparison of deduced amino acid sequence and the extensive similarity in the 5xe2x80x2 untranslated region, HCV has been classified as a separate genus in the Flaviviridae family, which also includes flaviviruses such as yellow fever virus and animal pestiviruses like bovine viral diarrhea virus and swine fever virus. All members of the Flaviviridae family have enveloped virions that contain a positive stranded RNA genome encoding all known virus-specific proteins via translation of a single, uninterrupted, open reading frame.
Considerable heterogeneity is found within the nucleotide and encoded amino acid sequence throughout the HCV genome. At least six major genotypes have been characterized, and more than 50 subtypes have been described. The major genotypes of HCV differ in their distribution worldwide, and the clinical significance of the genetic heterogeneity of HCV remains elusive despite numerous studies of the possible effect of genotypes on pathogenesis and therapy.
The RNA genome is about 9.6 Kb in length, and encodes a single polypeptide of about 3000 amino acids. The 5xe2x80x2 untranslated region contains an internal ribosome entry site (IRES), which directs cellular ribosomes to the correct AUG for initiation of translation. As was determined by transient expression of cloned HCV cDNAs, the precursor protein is cotranslationally and posttranslationally processed into at least 10 viral structural and nonstructural (NS) proteins by the action of a host signal peptidase and by two distinct viral proteinase activities. The translated product contains the following proteins: core-E1-E2-p7-NS2-NS3-NS4A-NS4B-NS5A-NS5B.
The N-terminal portion of NS3 functions as a proteolytic enzyme that is responsible for the cleavage of sites liberating the nonstructural proteins NS4A, NS4B, NS5A, and NS5B. NS3 has further been shown to be a serine protease. Although the functions of the NS proteins are not completely defined, it is known that NS4A is a protease cofactor and NS5B is an RNA polymerase involved in viral replication. Thus agents that inhibit NS3 proteolytic processing of the viral polyprotein are expected to have antiviral activity.
There are several patents which disclose HCV NS3 protease inhibitors. WO98/17679 describes peptide and peptidomimetic inhibitors with the following formula: Uxe2x80x94E8xe2x80x94E7-E6-E5-E4-NHxe2x80x94CH(CH2G1-W1, where W is one of a variety of electrophilic groups, including boronic acid or ester. E4 represents either an amino acid or one of a series of peptidomimetic groups, the sythesis of which are not exemplified. HCV protease inhibitors described in the present case are not covered.
Based on the large number of persons currently infected with HCV and the limited treatments available, it is desirable to discover new inhibitors of HCV NS3 protease.
Accordingly, one object of the present invention is to provide novel HCV NS3 protease inhibitors.
It is another object of the present invention to provide a novel method of treating HCV infection which comprises administering to a host in need of such treatment a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt form thereof.
It is another object of the present invention to provide pharmaceutical compositions with HCV NS3 protease inhibiting activity comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt form thereof. It is another object of the present invention to provide a method of inhibiting HCV present in a body fluid sample which comprises treating the body fluid sample with an effective amount of a compound of the present invention. It is another object of the present invention to provide a kit or container containing at least one of the compounds of the present invention in an amount effective for use as a standard or reagent in a test or assay for determining the ability of a potential pharmaceutical to inhibit HCV NS3 protease, HCV growth, or both.
It is another object of the present invention to provide novel compounds for use in therapy.
It is another object of the present invention to provide the use of novel compounds for the manufacture of a medicament for the treatment of HCV.
These and other objects, which will become apparent during the following detailed description, have been achieved by the inventors"" discovery that compounds of Formula (I): 
wherein W, R1, R2, R3, R8, R13, A1, A2, and A3 are defined below, stereoisomeric forms, mixtures of stereoisomeric forms, or pharmaceutically acceptable salt forms thereof, are effective HCV NS3 protease inhibitors.
[1] Thus, in a first embodiment, the present invention provides a novel compound of Formula I: 
or a stereoisomer or pharmaceutically acceptable salt form thereof, wherein;
A1 is xe2x80x94CH2xe2x80x94, xe2x80x94CH2CH2xe2x80x94, or xe2x80x94CH2CH2CH2xe2x80x94;
A2 is xe2x80x94Nxe2x95x90 or xe2x80x94CR6xe2x95x90;
A3 is selected from xe2x80x94R9, xe2x80x94A4xe2x80x94R9, xe2x80x94A4xe2x80x94A5xe2x80x94R9, and xe2x80x94A4xe2x80x94A5xe2x80x94A6xe2x80x94R9;
W is selected from the group
xe2x80x94B(OR26) (OR27),
xe2x80x94C(xe2x95x90O)C(xe2x95x90O)xe2x80x94Q,
xe2x80x94C(xe2x95x90O)C(xe2x95x90O)NHxe2x80x94Q,
xe2x80x94C(xe2x95x90O)C(xe2x95x90O)xe2x80x94Oxe2x80x94Q,
xe2x80x94C(xe2x95x90O)CF2C(xe2x95x90O)NHxe2x80x94Q,
xe2x80x94C(xe2x95x90O)CF3,
xe2x80x94C(xe2x95x90O)CF2CF3,
xe2x80x94C(xe2x95x90O)H,
an amino acid residue,
xe2x80x94A7xe2x80x94A8, and
xe2x80x94A7xe2x80x94A8xe2x80x94A9;
Q is selected from xe2x80x94(CR10R10c)txe2x80x94Q1, (CR10R10c)txe2x80x94Q2,
C1-C4 alkyl substituted with Q1,
C2-C4 alkenyl substituted with Q1,
C2-C4 alkynyl substituted with Q1,
an amino acid residue,
xe2x80x94A7xe2x80x94A8, and
xe2x80x94A7xe2x80x94A8xe2x80x94A9;
Q1 is selected from
xe2x80x94CO2R11, xe2x80x94SO2R11, xe2x80x94SO3R11, xe2x80x94P(O)2R11, xe2x80x94P(O)3R11,
aryl substituted with 0-4 Q1a,
5-6 membered heterocyclic group consisting of carbon atoms and 1-4 heteroatoms selected from the group:
O, S, and N, said heterocyclic group substituted with 0-4 Q1a;
Q1a is H, F, Cl, Br, I, xe2x80x94NO2, xe2x80x94CN, xe2x80x94NCS, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94CH3, xe2x80x94OCH3, xe2x80x94CO2R19, xe2x80x94C(xe2x95x90O)NR19R19, xe2x80x94NHC(xe2x95x90O)R19, xe2x80x94SO2R19, xe2x80x94SO2NR19R19, xe2x80x94NR19R19, xe2x80x94OR19, xe2x80x94SR19, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy
alternatively, NR19R19 may form a 5-6 membered heterocyclic group consisting of carbon atoms, a nitrogen atom, and optionally a second heteroatom selected from the group:
O, S, and N;
Q2 is xe2x80x94Xxe2x80x94NR12xe2x80x94Z, xe2x80x94NR12xe2x80x94Yxe2x80x94Z, or xe2x80x94Xxe2x80x94NR12xe2x80x94Yxe2x80x94Z;
X is selected from the group: xe2x80x94C(xe2x95x90O)xe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94S(xe2x95x90O)xe2x80x94, xe2x80x94S(xe2x95x90O)2xe2x80x94, xe2x80x94P(O)xe2x80x94, xe2x80x94P(O)2xe2x80x94, and xe2x80x94P(O)3xe2x80x94;
Y is selected from the group: xe2x80x94C(xe2x95x90O)xe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94S(xe2x95x90O)xe2x80x94, xe2x80x94S(xe2x95x90O)2xe2x80x94, xe2x80x94P(O)xe2x80x94, xe2x80x94P(O)2xe2x80x94, and xe2x80x94P(O)3xe2x80x94;
Z is C1-C4 haloalkyl,
C1-C4 alkyl substituted with 0-3 Za,
C2-C4 alkenyl substituted with 0-3 Za,
C2-C4 alkynyl substituted with 0-3 Za,
C3-C10 cycloalkyl substituted with 0-5 Zb,
C3-C10 carbocyle substituted with 0-5 Zb,
aryl substituted with 0-5 Zb,
5-10 membered heterocyclic group consisting of carbon atoms and 1-4 heteroatoms selected from the group:
O, S, and N, said heterocyclic group substituted with 0-4 Zb;
an amino acid residue,
xe2x80x94A7xe2x80x94A8, or
xe2x80x94A7xe2x80x94A8xe2x80x94A9;
Za is H, F, Cl, Br, I, xe2x80x94NO2, xe2x80x94CN, xe2x80x94NCS, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94CH3, xe2x80x94OCH3, xe2x80x94CO2R20, xe2x80x94C(xe2x95x90O)NR20R20, xe2x80x94NHC(xe2x95x90O)R20, xe2x80x94NR20R20, xe2x80x94OR20, xe2x80x94SR20, xe2x80x94S(xe2x95x90O)R20, xe2x80x94SO2R20, xe2x80x94SO2NR20R20, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy,
C3-C10 cycloalkyl substituted with 0-5 Zb,
C3-C10 carbocyle substituted with 0-5 Zb,
aryl substituted with 0-5 Zb, or
5-10 membered heterocyclic group consisting of carbon atoms and 1-4 heteroatoms selected from the group: O, S, and N, said heterocyclic group substituted with 0-4 Zb;
Zb is H, F, Cl, Br, I, xe2x80x94NO2, xe2x80x94CN, xe2x80x94NCS, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94CH3, xe2x80x94OCH3, xe2x80x94CO2R20, xe2x80x94C(xe2x95x90O)NR20R20, xe2x80x94NHC(xe2x95x90O)R20, xe2x80x94NR20R20, xe2x80x94OR20, xe2x80x94SR20, xe2x80x94S(xe2x95x90O)R20, xe2x80x94SO2R20, xe2x80x94SO2NR20R20, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy,
C3-C10 cycloalkyl substituted with 0-5 Zc,
C3-C10 carbocyle substituted with 0-5 Zc,
aryl substituted with 0-5 Zc, or
5-10 membered heterocyclic group consisting of carbon atoms and 1-4 heteroatoms selected from the group:
O, S, and N, said heterocyclic group substituted with 0-4 Zc;
Zc is H, F, Cl, Br, I, xe2x80x94NO2, xe2x80x94CN, xe2x80x94NCS, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94CH3, xe2x80x94OCH3, xe2x80x94CO2R20, xe2x80x94C(xe2x95x90O)NR20R20, xe2x80x94NHC(xe2x95x90O)R20, xe2x80x94NR20R20, xe2x80x94OR20, xe2x80x94SR20, xe2x80x94S(xe2x95x90O)R20, xe2x80x94SO2R20, xe2x80x94SO2NR20R20, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy;
alternatively, NR20R20 may form a 5-6 membered heterocyclic group consisting of carbon atoms, a nitrogen atom, and optionally a second heteroatom selected from the group:
O, S, and N;
OR26 and OR27 are independently selected from:
a) xe2x80x94OH,
b) xe2x80x94F,
c) xe2x80x94NR28R29,
d) C1-C8 alkoxy, or
when taken together, OR26 and OR27 form:
e) a cyclic boron ester where said chain or ring contains from 2 to 20 carbon atoms, and, optionally, 1, 2, or 3 heteroatoms which can be N, S, or O,
f) a cyclic boron amide where said chain or ring contains from 2 to 20 carbon atoms and, optionally, 1, 2, or 3 heteroatoms which can be N, S, or O,
g) a cyclic boron amide-ester where said chain or ring contains from 2 to 20 carbon atoms and, optionally, 1, 2, or 3 heteroatoms which can be N, S, or O;
R1 is selected from the group: H, F,
C1-C6 alkyl substituted with 0-3 R1a,
C2-C6 alkenyl substituted with 0-3 R1a,
C2-C6 alkynyl substituted with 0-3 R1a,
aryl substituted with 0-5 R1a, and
C3-C6 cycloalkyl substituted with 0-3 R1a;
R1a is selected at each occurrence from the group:
Cl, F, Br, I, CF3, CHF2, OH, xe2x95x90O, SH, xe2x80x94CO2R1b, xe2x80x94SO2R1b, xe2x80x94SO3R1b, xe2x80x94P(O)2R1b, xe2x80x94P(O)3R1b, xe2x80x94C (xe2x95x90O)NHR1b, xe2x80x94NHC(xe2x95x90O)R1b, xe2x80x94SO2NHR1b, xe2x80x94OR1b, xe2x80x94SR1b, C1-C3 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, xe2x80x94Sxe2x80x94(C1-C6 alkyl),
aryl substituted with 0-5 R1c,
xe2x80x94Oxe2x80x94(CH2)q-aryl substituted with 0-5 R1c,
xe2x80x94Sxe2x80x94(CH2)q-aryl substituted with 0-5 R1c,
5-10 membered heterocyclic group consisting of carbon atoms and 1-4 heteroatoms selected from the group:
O, S, and N, and substituted with 0-3 R1c;
R1b is H,
C1-C4 alkyl substituted with 0-3 R1c,
C2-C4 alkenyl substituted with 0-3 R1c,
C2-C4 alkynyl substituted with 0-3 R1c,
C3-C6 cycloalkyl substituted with 0-5 R1c,
C3-C6 carbocyle substituted with 0-5 R1c,
aryl substituted with 0-5 R1c,
5-6 membered heterocyclic group consisting of carbon atoms and 1-4 heteroatoms selected from the group:
O, S, and N, said heterocyclic group substituted with 0-4 R1c;
R1c is selected at each occurrence from the group:
C1-C4 alkyl, Cl, F, Br, I, OH, C1-C4 alkoxy, xe2x80x94CN, xe2x80x94NO2, xe2x80x94OR1d, xe2x80x94(xe2x95x90O)OR1d, xe2x80x94NR1dR1d, xe2x80x94CF3, xe2x80x94OCF3, and aryl substituted by 0-3 R1e;
R1d is H, C1-C4 alkyl, phenyl or benzyl;
R1e is selected at each occurrence from the methyl, ethyl, Cl, F, Br, I, OH, methoxy, ethoxy, xe2x80x94CN, xe2x80x94NO2, xe2x80x94C(xe2x95x90O)OR1d, NR1dR1d, CF3, and OCF3;
R2 is H, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, or C3-C4 cycloalkyl;
R3 is xe2x80x94R4, xe2x80x94NR4R5, xe2x80x94OR4, or xe2x80x94SR4;
R4 is selected from the group: H,
C1-C8 alkyl substituted with 0-3 R4a,
C2-C8 alkenyl substituted with 0-3 R4a,
C2-C8 alkynyl substituted with 0-3 R4a,
C3-C10 cycloalkyl substituted with 0-4 R4b,
aryl substituted with 0-5 R4b,
5-10 membered heterocyclic group consisting of carbon atoms and 1-4 heteroatoms selected from the group:
O, S, and N, and said heterocyclic group is substituted with 0-3 R4b;
R4a is, at each occurrence, independently selected from:
H, F, Cl, Br, I, xe2x80x94NO2, xe2x80x94CN, xe2x80x94NCS, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94CH3, xe2x80x94OCH3, xe2x95x90O, OH, xe2x80x94CO2H, phenyl, xe2x80x94C(xe2x95x90NH)NH2, xe2x80x94NH2, xe2x80x94NH(CH3), xe2x80x94N(CH3)2,
xe2x80x94CO2R11, xe2x80x94C(xe2x95x90O)NR11R11, xe2x80x94NHC(xe2x95x90O)R11, xe2x80x94NR11R11, OR11a, xe2x80x94SR11a, xe2x80x94C(xe2x95x90O)R11a, xe2x80x94S(xe2x95x90O)R11a, xe2x80x94SO2R11, xe2x80x94SO2NR11R11, C1-C4 haloalkyl, C1-C4 haloalkoxy,
C3-C10 cycloalkyl substituted with 0-4 R4b,
aryl substituted with 0-5 R4b, and
5-10 membered heterocyclic group consisting of carbon atoms and 1-4 heteroatoms selected from the group:
O, S, and N, and said heterocyclic group is substituted with 0-3 R4b;
R4b is, at each occurrence, independently selected from:
H, F, Cl, Br, I, xe2x80x94NO2, xe2x80x94CN, xe2x80x94NCS, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94CH3, xe2x80x94OCH3, xe2x95x90O, OH, xe2x80x94CO2H, phenyl, xe2x80x94C(xe2x95x90NH)NH2, xe2x80x94NH2, xe2x80x94NH(CH3), xe2x80x94N(CH3)2,
xe2x80x94CO2R11, xe2x80x94C(xe2x95x90O)NR11R11, xe2x80x94NHC(xe2x95x90O)R11, xe2x80x94NR11R11, xe2x80x94OR11a, xe2x80x94SR11a, xe2x80x94C(xe2x95x90O)R11a, xe2x80x94S(xe2x95x90O)R11a, xe2x80x94SO2R11, xe2x80x94SO2NR11R11, C1-C4 haloalkyl, C1-C4 haloalkoxy,
C1-C6 alkyl substituted with 0-3 R4c,
C2-C6 alkenyl substituted with 0-3 R4c,
C2-C6 alkynyl substituted with 0-3 R4c,
C3-C6 cycloalkyl substituted with 0-4 R4d,
aryl substituted with 0-5 R4d, and
5-10 membered heterocyclic group consisting of carbon atoms and 1-4 heteroatoms selected from the group:
O, S, and N, and said heterocyclic group is substituted with 0-3 R4d;
R4c is, at each occurrence, independently selected from:
H, F, Cl, Br, I, xe2x80x94NO2, xe2x80x94CN, xe2x80x94NCS, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94CH3, xe2x80x94OCH3, xe2x95x90O, OH, xe2x80x94CO2H, phenyl, xe2x80x94C(xe2x95x90NH)NH2, xe2x80x94NH2, xe2x80x94NH(CH3), xe2x80x94N(CH3)2,
xe2x80x94CO2R11, xe2x80x94C(xe2x95x90O)NR11R11, xe2x80x94NHC(xe2x95x90O)R11, xe2x80x94NR11R11, OR11a, xe2x80x94SR11a, xe2x80x94C(xe2x95x90O)R11a, xe2x80x94S(xe2x95x90O)R11a, xe2x80x94SO2R11, xe2x80x94SO2NR11R11, C1-C4 haloalkyl, C1-C4 haloalkoxy,
C3-C6 cycloalkyl substituted with 0-4 R4d,
aryl substituted with 0-5 R4d,
5-10 membered heterocyclic group consisting of carbon atoms and 1-4 heteroatoms selected from the group:
O, S, and N, and said heterocyclic group is substituted with 0-3 R4d;
R4d is, at each occurrence, independently selected from:
H, F, Cl, Br, I, xe2x80x94NO2, xe2x80x94CN, xe2x80x94NCS, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94CH3, xe2x80x94OCH3, xe2x95x90O, OH, xe2x80x94CO2H, phenyl, xe2x80x94NH2, xe2x80x94NH(CH3), xe2x80x94N(CH3)2, xe2x80x94CO2R11, xe2x80x94C(xe2x95x90O)NR11R11, xe2x80x94NHC(xe2x95x90O)R11, xe2x80x94NR11R11, xe2x80x94OR11a, xe2x80x94SR11a, xe2x80x94C(xe2x95x90O)R11a, xe2x80x94S(xe2x95x90O)R11a, xe2x80x94SO2R11, xe2x80x94SO2NR11R11, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy;
R5 is selected from the group: H, C1-C6 alkyl, phenyl, phenylmethyl-, phenylethyl-, C3-C6 cycloalkyl, C3-C6 cycloalkylmethyl-, and C3-C6 cycloalkylethyl-;
R6 is selected from the group: H, F, Cl, Br, I,
C1-C6 alkyl substituted with 0-3 R6a,
C2-C6 alkenyl substituted with 0-3 R6a,
C2-C6 alkynyl substituted with 0-3 R6a,
C3-C6 cycloalkyl substituted with 0-4 R6b,
aryl substituted with 0-5 R6b,
5-6 membered heterocyclic group consisting of carbon atoms and 1-4 heteroatoms selected from the group:
O, S, and N, and said heterocyclic group is substituted with 0-3 R6b;
R6a is selected from the group: H, F, Cl, Br, I, xe2x80x94CO2R11, xe2x80x94NR11R11, xe2x80x94OR11, xe2x80x94SR11, xe2x80x94C(xe2x95x90NH)NH2,
C3-C6 cycloalkyl substituted with 0-4 R6b,
aryl substituted with 0-5 R6b,
5-6 membered heterocyclic group consisting of carbon atoms and 1-4 heteroatoms selected from the group:
O, S, and N, and said heterocyclic group is substituted with 0-3 R6b;
R6b is selected from the group: H, F, Cl, Br, I, xe2x80x94CO2R11, xe2x80x94NR11R11, xe2x80x94OR11, xe2x80x94SR11, xe2x80x94C(xe2x95x90NH)NH2;
C1-C6 alkyl substituted with 0-3 R6c,
C2-C6 alkenyl substituted with 0-3 R6c,
C2-C6 alkynyl substituted with 0-3 R6c,
C3-C6 cycloalkyl substituted with 0-4 R6d,
aryl substituted with 0-5 R6d,
5-6 membered heterocyclic group consisting of carbon atoms and 1-4 heteroatoms selected from the group:
O, S, and N, and said heterocyclic group is substituted with 0-3 R6d;
R6c is selected from the group: H, F, Cl, Br, I, xe2x80x94CO2R11, xe2x80x94NR11R11, xe2x80x94OR11, xe2x80x94SR11, xe2x80x94C(xe2x95x90NH)NH2,
C3-C6 cycloalkyl substituted with 0-4 R6d,
aryl substituted with 0-5 R6d,
5-6 membered heterocyclic group consisting of carbon atoms and 1-4 heteroatoms selected from the group:
O, S, and N, and said heterocyclic group is substituted with 0-3 R6d;
R6d is selected from the group: H, F, Cl, Br, I, xe2x80x94CO2R11, xe2x80x94NR11R11, xe2x80x94OR11, xe2x80x94SR11, xe2x80x94C(xe2x95x90NH)NH2;
R8 is H, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, or C3-C4 cycloalkyl;
R9 is selected from the group: xe2x80x94S(xe2x95x90O)R9a, xe2x80x94S(xe2x95x90O)2R9a, xe2x80x94C(xe2x95x90O)R9a, xe2x80x94C(xe2x95x90O)OR9a, xe2x80x94C(xe2x95x90O)NHR9a, C1-C3 alkyl-R9a, C2-C6 alkenyl-R9a, and C2-C6 alkynyl-R9a;
R9a is selected from the group: H
C1-C6 alkyl substituted with 0-3 R9b,
C3-C6 cycloalkyl substituted with 0-3 R9c and
aryl substituted with 0-3 R9c and
5-14 membered heterocyclic group consisting of carbon atoms and 1-4 heteroatoms selected from the group:
O, S, and N, and said heterocyclic group is substituted with 0-3 R9c;
R9b is selected from the group:
phenyl substituted with 0-3 R9c,
naphthyl substituted with 0-3 R9c,
benzyl substituted with 0-3 R9c, and
5-10 membered heterocyclic group consisting of carbon atoms and 1-4 heteroatoms selected from the group:
O, S, and N; and said heterocyclic group is substituted with 0-3 R9c;
R9c is selected at each occurrence from the group:
H, F, Cl, Br, I, xe2x80x94NO2, xe2x80x94CN, xe2x80x94NCS, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94CH3, xe2x80x94OCH3, xe2x95x90O, OH, xe2x80x94CO2H, phenyl, xe2x80x94NH2, xe2x80x94NH(CH3), xe2x80x94N(CH3)2, xe2x80x94CO2R11, xe2x80x94C(xe2x95x90O)NR11R11, xe2x80x94NHC(xe2x95x90O)R11, xe2x80x94NR11R11, OR11a, xe2x80x94SR11a, C(xe2x95x90O)R11a, xe2x80x94S(xe2x95x90O)R11a, xe2x80x94SO2R11, xe2x80x94SO2NR11R11, C1-C4 haloalkyl, C1-C4 haloalkoxy,
C1-C4 alkyl substituted with 0-3 R9d,
C1-C4 alkoxy substituted with 0-3 R9d,
C3-C6 cycloalkyl substituted with 0-3 R9d,
aryl substituted with 0-5 R9d, and
5-6 membered heterocyclic group consisting of carbon atoms and 1-4 heteroatoms selected from the group:
O, S, and N, and said heterocyclic group is substituted with 0-4 R9d;
R9d is selected at each occurrence from the group:
H, F, Cl, Br, I, xe2x80x94NO2, xe2x80x94CN, xe2x80x94NCS, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94CH3, xe2x80x94OCH3, xe2x95x90O, OH, xe2x80x94CO2H, phenyl, xe2x80x94NH2, xe2x80x94NH(CH3), xe2x80x94N(CH3)2, xe2x80x94CO2R11, xe2x80x94C(xe2x95x90O)NR11R11, xe2x80x94NHC(xe2x95x90O)R11, xe2x80x94NR11R11, OR11a, xe2x80x94SR11a, xe2x80x94C(xe2x95x90O)R11a, xe2x80x94S(xe2x95x90O)R11a, xe2x80x94SO2R11, xe2x80x94SO2NR11R11, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy;
R10 is selected from the group: xe2x80x94CO2R11, xe2x80x94NR11R11, and C1-C6 alkyl substituted with 0-1 R10a;
R10ais selected from the group: halo, xe2x80x94NO2, xe2x80x94CN, xe2x80x94CF3, xe2x80x94CO2R11, xe2x80x94NR11R11, xe2x80x94OR11, xe2x80x94SR11, xe2x80x94C(xe2x95x90NH)NH2, and aryl substituted with 0-1 R10b;
R10b is selected from the group: xe2x80x94CO2H, xe2x80x94NH2, xe2x80x94OH, xe2x80x94SH, and xe2x80x94C(xe2x95x90NH)NH2;
R10c is H or C1-C4 alkyl;
alternatively, R10 and R10c can be combined to form a C3-C6 cycloalkyl group substituted with 0-1 R10a;
R11 is, at each occurrence, independently H or C1-C4 alkyl;
R11a is, at each occurrence, independently H, C1-C4 alkyl, aryl, or C1-C4 haloalkyl;
R12 is H or C1-C4 alkyl;
R13 is H or C1-C4 alkyl;
R19 is C1-C4 alkyl, C1-C4 haloalkyl, aryl, aryl(C1-C4 alkyl), C3-C6 cycloalkyl, or C3-C6 cycloalkyl(C1-C4 alkyl);
R20 is H, C1-C4 alkyl, C1-C4 haloalkyl, aryl, aryl(C1-C4 alkyl)xe2x80x94, C3-C6 cycloalkyl, or C3-C6 cycloalkyl(C1C4 alkyl)-;
R28 and R29, are independently selected from: H, C1-C4 alkyl, aryl(C1-C4 alkyl)-, and C3-C7 cycloalkyl;
A4, A5, A6, A7, A8, and A9 are independently selected from an amino acid residue;
an amino acid residue, at each occurence, independently comprises a natural amino acid, a modified amino acid or an unnatural amino acid wherein said natural, modified or unnatural amino acid is of either D or L configuration;
t is 1, 2, 3, or 4; and
q is 0, 1 or 2.
[2] In a preferred embodiment, the present invention provides a novel compound of Formula (Ia), (Ib), or (Ic): 
or a stereoisomer or pharmaceutically acceptable salt form thereof.
[3] In a more preferred embodiment, the present invention provides a compound of Formula (Ia): 
or a stereoisomer or pharmaceutically acceptable salt form thereof, wherein:
A3 is selected from xe2x80x94R9, xe2x80x94A4xe2x80x94R9, and xe2x80x94A4xe2x80x94A5xe2x80x94R9;
W is selected from the group
xe2x80x94B(OR26) (OR27),
xe2x80x94C(xe2x95x90O)C(xe2x95x90O)xe2x80x94Q,
xe2x80x94C(xe2x95x90O)C(xe2x95x90O)NHxe2x80x94Q,
xe2x80x94C(xe2x95x90O)C(xe2x95x90O)xe2x80x94Oxe2x80x94Q,
xe2x80x94C(xe2x95x90O)CF2C(xe2x95x90O)NHxe2x80x94Q,
xe2x80x94C(xe2x95x90O)CF3,
xe2x80x94C(xe2x95x90O)CF2CF3,
xe2x80x94C(xe2x95x90O)H,
an amino acid residue,
xe2x80x94A7xe2x80x94A8, and
xe2x80x94A7xe2x80x94A8xe2x80x94A9;
Q is selected from xe2x80x94(CR10R10c)txe2x80x94Q1, xe2x80x94(CR10R10c)txe2x80x94Q2,
C1-C4 alkyl substituted with Q1,
C2-C4 alkenyl substituted with Q1,
C2-C4 alkynyl substituted with Q1,
an amino acid residue,
xe2x80x94A7xe2x80x94A8, and
xe2x80x94A7xe2x80x94A8xe2x80x94A9;
Q1 is selected from
xe2x80x94CO2R11, xe2x80x94SO2R11, xe2x80x94SO3R11, xe2x80x94P(O)2R11, xe2x80x94P(O)3R11,
aryl substituted with 0-4 Q1a,
5-6 membered heterocyclic group consisting of carbon atoms and 1-4 heteroatoms selected from the group:
O, S, and N, said heterocyclic group substituted with 0-4 Q1a;
Q1a is H, F, Cl, Br, I, xe2x80x94NO2, xe2x80x94CN, xe2x80x94NCS, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94CH3, xe2x80x94OCH3, xe2x80x94CO2R19, xe2x80x94C(xe2x95x90O)NR19R19, xe2x80x94NHC(xe2x95x90O)R19, xe2x80x94SO2R19, xe2x80x94SO2NR19R19, xe2x80x94NR19R19, xe2x80x94OR19, xe2x80x94SR19, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy
alternatively, NR19R19 may form a 5-6 membered heterocyclic group consisting of carbon atoms, a nitrogen atom, and optionally a second heteroatom selected from the group:
O, S, and N;
Q2 is xe2x80x94Xxe2x80x94NR12xe2x80x94Z, xe2x80x94NR12xe2x80x94Yxe2x80x94Z, or xe2x80x94Xxe2x80x94NR12xe2x80x94Yxe2x80x94Z;
X is selected from the group: xe2x80x94C(xe2x95x90O)xe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94S(xe2x95x90O)xe2x80x94, xe2x80x94S(xe2x95x90O)2xe2x80x94, xe2x80x94P(O)xe2x80x94, xe2x80x94P(O)2xe2x80x94, and xe2x80x94P(O)3xe2x80x94;
Y is selected from the group: xe2x80x94C(xe2x95x90O)xe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94S(xe2x95x90O)xe2x80x94, xe2x80x94S(xe2x95x90O)2xe2x80x94, xe2x80x94P(O)xe2x80x94, xe2x80x94P(O)2xe2x80x94, and xe2x80x94P(O)3xe2x80x94;
Z is C1-C4 haloalkyl,
C1-C4 alkyl substituted with 0-3 Za,
C2-C4 alkenyl substituted with 0-3 Za,
C2-C4 alkynyl substituted with 0-3 Za,
C3-C10 cycloalkyl substituted with 0-5 Zb,
C3-C10 carbocyle substituted with 0-5 Zb,
aryl substituted with 0-5 Zb,
5-10 membered heterocyclic group consisting of carbon atoms and 1-4 heteroatoms selected from the group:
O, S, and N, said heterocyclic group substituted with 0-4 Zb;
an amino acid residue,
xe2x80x94A7xe2x80x94A8, or
xe2x80x94A7xe2x80x94A8xe2x80x94A9;
Z0 is H, F, Cl, Br, I, xe2x80x94NO2, xe2x80x94CN, xe2x80x94NCS, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94CH3, xe2x80x94OCH3, xe2x80x94CO2R20, xe2x80x94C(xe2x95x90O)NR20R20, xe2x80x94NHC(xe2x95x90O)R20, xe2x80x94NR20R20, xe2x80x94OR20, xe2x80x94SR20, xe2x80x94S(xe2x95x90O)R20, xe2x80x94SO2R20, xe2x80x94SO2NR20R20, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy,
C3-C10 cycloalkyl substituted with 0-5 Zb,
C3-C10 carbocyle substituted with 0-5 Zb,
aryl substituted with 0-5 Zb, or
5-10 membered heterocyclic group consisting of carbon atoms and 1-4 heteroatoms selected from the group:
O, S, and N, said heterocyclic group substituted with 0-4 Zb;
Zb is H, F, Cl, Br, I, xe2x80x94NO2, xe2x80x94CN, xe2x80x94NCS, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94CH3, xe2x80x94OCH3, xe2x80x94CO2R20, xe2x80x94C(xe2x95x90O)NR20R20, xe2x80x94NHC(xe2x95x90O)R20, xe2x80x94NR20R20, xe2x80x94OR20, xe2x80x94SR20, xe2x80x94S(xe2x95x90O)R20, xe2x80x94SO2R20, xe2x80x94SO2NR20R20, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy,
C3-C10 cycloalkyl substituted with 0-5 Zc,
C3-C10 carbocyle substituted with 0-5 Zc,
aryl substituted with 0-5 Zc, or
5-10 membered heterocyclic group consisting of carbon atoms and 1-4 heteroatoms selected from the group:
O, S, and N, said heterocyclic group substituted with 0-4 Zc;
Zc is H, F, Cl, Br, I, xe2x80x94NO2, xe2x80x94CN, xe2x80x94NCS, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94CH3, xe2x80x94OCH3, xe2x80x94CO2R20, xe2x80x94C(xe2x95x90O)NR20R20, xe2x80x94NHC(xe2x95x90O)R20, xe2x80x94NR20R20, xe2x80x94OR20, xe2x80x94SR20, xe2x80x94S(xe2x95x90O)R20, xe2x80x94SO2R20, xe2x80x94SO2NR20R20, xe2x80x94C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy;
alternatively, NR20R20 may form a 5-6 membered heterocyclic group consisting of carbon atoms, a nitrogen atom, and optionally a second heteroatom selected from the group:
O, S, and N;
OR26 and OR27 are independently selected from:
a) xe2x80x94OH,
b) xe2x80x94F,
c) xe2x80x94NR28R29,
d) C1-C8 alkoxy, or
when taken together, OR26 and OR27 form:
e) a cyclic boron ester where said chain or ring contains from 2 to 20 carbon atoms, and, optionally, 1, 2, or 3 heteroatoms which can be N, S, or O,
f) a cyclic boron amide where said chain or ring contains from 2 to 20 carbon atoms and, optionally, 1, 2, or 3 heteroatoms which can be N, S, or O,
g) a cyclic boron amide-ester where said chain or ring contains from 2 to 20 carbon atoms and, optionally, 1, 2, or 3 heteroatoms which can be N, S, or O;
R1 is selected from the group: H, F,
C1-C6 alkyl substituted with 0-3 R1a,
C2-C6 alkenyl substituted with 0-3 R1a,
C2-C6 alkynyl substituted with 0-3 R1a,
aryl substituted with 0-5 R1a, and
C3-C6 cycloalkyl substituted with 0-3 R1a;
R1a is selected at each occurrence from the group:
Cl, F, Br, I, CF3, CHF2, OH, xe2x95x90O, SH, xe2x80x94CO2R1b, xe2x80x94SO2R1b, xe2x80x94SO3R1b, xe2x80x94P(O)2R1b, xe2x80x94P(O)3R1b, xe2x80x94C(xe2x95x90O)NHR1b, xe2x80x94NHC(xe2x95x90O)R1b, xe2x80x94SO2NHR1b, xe2x80x94OR1b, xe2x80x94SR1b, C1-C3 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, xe2x80x94Sxe2x80x94(C1-C6 alkyl),
aryl substituted with 0-5 R1c,
xe2x80x94Oxe2x80x94(CH2)q-aryl substituted with 0-5 R1c,
xe2x80x94Sxe2x80x94(CH2)q-aryl substituted with 0-5 R1c,
5-10 membered heterocyclic group consisting of carbon atoms and 1-4 heteroatoms selected from the group:
O, S, and N, and substituted with 0-3 R1c;
R1b is H,
C1-C4 alkyl substituted with 0-3 R1c,
C2-C4 alkenyl substituted with 0-3 R1c,
C2-C4 alkynyl substituted with 0-3 R1c,
C3-C6 cycloalkyl substituted with 0-5 R1c,
C3-C6 carbocyle substituted with 0-5 R1c,
aryl substituted with 0-5 R1c,
5-6 membered heterocyclic group consisting of carbon atoms and 1-4 heteroatoms selected from the group:
O, S, and N, said heterocyclic group substituted with 0-4 R1c;
R1c is selected at each occurrence from the group:
C1-C4 alkyl, Cl, F, Br, I, OH, C1-C4 alkoxy, xe2x80x94CN, xe2x80x94NO2, xe2x80x94OR1d, xe2x80x94C(xe2x95x90O)OR1d, NR1dR1d, CF3, OCF3, and aryl substituted by 0-3 R1e;
R1d is H, methyl, ethyl, propyl, butyl, phenyl, or benzyl;
R1e is selected at each occurrence from the methyl, ethyl, Cl, F, Br, I, OH, methoxy, ethoxy, xe2x80x94CN, xe2x80x94NO2, xe2x80x94C(xe2x95x90O)OR1d, NR1dR1d, CF3, and OCF3;
R2 is H, methyl, ethyl, propyl, butyl, or cyclopropyl;
R3 is xe2x80x94R4, xe2x80x94NR4R5, xe2x80x94OR4, or xe2x80x94SR4;
R4 is selected from the group: H,
C1-C8 alkyl substituted with 0-3 R4a,
C2-C8 alkenyl substituted with 0-3 R4a,
C2-C8 alkynyl substituted with 0-3 R4a,
C3-C10 cycloalkyl substituted with 0-4 R4b,
aryl substituted with 0-5 R4b,
5-10 membered heterocyclic group consisting of carbon atoms and 1-4 heteroatoms selected from the group:
O, S, and N, and said heterocyclic group is substituted with 0-3 R4b;
R4a is, at each occurrence, independently selected from:
H, F, Cl, Br, I, xe2x80x94NO2, xe2x80x94CN, xe2x80x94NCS, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94CH3, xe2x80x94OCH3, xe2x95x90O, OH, xe2x80x94CO2H, phenyl, xe2x80x94C(xe2x95x90NH)NH2, xe2x80x94NH2, xe2x80x94NH(CH3), xe2x80x94N(CH3)2,
xe2x80x94CO2R11, xe2x80x94C(xe2x95x90O)NR11R11, xe2x80x94NHC(xe2x95x90O)R11, xe2x80x94NR11R11, OR11a, xe2x80x94SR11a, xe2x80x94C(xe2x95x90O)R11a, xe2x80x94S(xe2x95x90O)R11a, xe2x80x94SO2R11, xe2x80x94SO2NR11R11, C1-C4 haloalkyl, C1-C4 haloalkoxy,
C3-C10 cycloalkyl substituted with 0-4 R4b,
aryl substituted with 0-5 R4b, and 5-10 membered heterocyclic group consisting of carbon atoms and 1-4 heteroatoms selected from the group:
O, S, and N, and said heterocyclic group is substituted with 0-3 R4b;
R4b is, at each occurrence, independently selected from:
H, F, Cl, Br, I, xe2x80x94NO2, xe2x80x94CN, xe2x80x94NCS, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94CH3,
OCH3, xe2x95x90O, OH, xe2x80x94CO2H, phenyl, xe2x80x94C(xe2x95x90NH)NH2, xe2x80x94NH2,
xe2x80x94NH(CH3), xe2x80x94N(CH3)2, xe2x80x94CO2R11, xe2x80x94C(xe2x95x90O)NR11R11, xe2x80x94NHC(xe2x95x90O)R11, xe2x80x94NR11R11, xe2x80x94OR11a,
SR11a, xe2x80x94C(xe2x95x90O)R11a, xe2x80x94S(xe2x95x90O)R11a, xe2x80x94SO2R11, xe2x80x94SO2NR11R11,
C1-C4 haloalkyl, C1-C4 haloalkoxy,
C1-C6 alkyl substituted with 0-3 R4c,
C2-C6 alkenyl substituted with 0-3 R4c,
C2-C6 alkynyl substituted with 0-3 R4c,
C3-C6 cycloalkyl substituted with 0-4 R4d,
aryl substituted with 0-5 R4d, and
5-10 membered heterocyclic group consisting of carbon atoms and 1-4 heteroatoms selected from the group:
O, S, and N, and said heterocyclic group is substituted with 0-3 R4d;
R4c is, at each occurrence, independently selected from:
H, F, Cl, Br, I, xe2x80x94NO2, xe2x80x94CN, xe2x80x94NCS, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94CH3, xe2x80x94OCH3, xe2x95x90O, OH, xe2x80x94CO2H, phenyl, xe2x80x94C(xe2x95x90NH)NH2, xe2x80x94NH2, xe2x80x94NH(CH3), xe2x80x94N(CH3)2,
xe2x80x94CO2R11, xe2x80x94C(xe2x95x90O)NR11R11, xe2x80x94NHC(xe2x95x90O)R11, xe2x80x94NR11R11, OR11a, xe2x80x94SR11a, xe2x80x94C(xe2x95x90O)R11a, S(xe2x95x90O)R11a, xe2x80x94SO2R11, xe2x80x94SO2NR11R11, C1-C4 haloalkyl, C1-C4 haloalkoxy,
C3-C6 cycloalkyl substituted with 0-4 R4d,
aryl substituted with 0-5 R4d,
5-10 membered heterocyclic group consisting of carbon atoms and 1-4 heteroatoms selected from the group:
O, S, and N, and said heterocyclic group is substituted with 0-3 R4d;
R4d is, at each occurrence, independently selected from:
H, F, Cl, Br, I, xe2x80x94NO2, xe2x80x94CN, xe2x80x94NCS, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94CH3, xe2x80x94OCH3, xe2x95x90O, OH, xe2x80x94CO2H, phenyl, xe2x80x94NH2, xe2x80x94NH(CH3), -N(CH3)2, xe2x80x94CO2R11, xe2x80x94C(xe2x95x90O)NR11R11, xe2x80x94NHC(xe2x95x90O)R11, xe2x80x94NR11R11, OR11a, xe2x80x94SR11a, C(xe2x95x90O)R11a, xe2x80x94S(xe2x95x90O)R11a, xe2x80x94SO2R11, xe2x80x94SO2NR11R11, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy;
R5 is selected from the group: H, C1-C6 alkyl, phenyl, phenylmethyl-, phenylethyl-, C3-C6 cycloalkyl, C3-C6 cycloalkylmethyl-, and C3-C6 cycloalkylethyl-;
R6 is H, Cl, Br, methyl, ethyl, or cyclopropyl;
R8 is H, methyl, ethyl, propyl, butyl, or cyclopropyl;
R9 is selected from the group: xe2x80x94S(xe2x95x90O)R9a, xe2x80x94S(xe2x95x90O)2R9a, xe2x80x94C(xe2x95x90O)R9a, xe2x80x94C(xe2x95x90O)OR9a, xe2x80x94C(xe2x95x90O)NHR9a, C1-C3 alkyl-R9a, C2-C6 alkenyl-R9a, and C2-C6 alkynyl-R9a;
R9a is selected from the group:
H C1-C6 alkyl substituted with 0-3 R9b,
C3-C6 cycloalkyl substituted with 0-3 R9c and
aryl substituted with 0-3 R9c and
5-14 membered heterocyclic group consisting of carbon atoms and 1-4 heteroatoms selected from the group:
O, S, and N, and said heterocyclic group is substituted with 0-3 R9c;
R9b is selected from the group:
phenyl substituted with 0-3 R9c,
naphthyl substituted with 0-3 R9c,
benzyl substituted with 0-3 R9c, and
5-10 membered heterocyclic group consisting of carbon atoms and 1-4 heteroatoms selected from the group:
O, S, and N; and said heterocyclic group is substituted with 0-3 R9c;
R9c is selected at each occurrence from the group:
H, F, Cl, Br, I, xe2x80x94NO2, xe2x80x94CN, xe2x80x94NCS, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94CH3,
xe2x80x94OCH3, xe2x95x90O, OH, xe2x80x94CO2H, phenyl, xe2x80x94NH2, xe2x80x94NH(CH3), xe2x80x94N(CH3)2, xe2x80x94CO2R11, xe2x80x94C(xe2x95x90O)NR11R11, xe2x80x94NHC(xe2x95x90O)R11, xe2x80x94NR11R11a, xe2x80x94OR11a, xe2x80x94SR11a, xe2x80x94C(xe2x95x90O)R11a, xe2x80x94S(xe2x95x90O)R11a, xe2x80x94SO2R11, xe2x80x94SO2NR11R11, C1-C4 haloalkyl, C1-C4 haloalkoxy,
C1-C4 alkyl substituted with 0-3 R9d,
C1-C4 alkoxy substituted with 0-3 R9d,
C3-C6 cycloalkyl substituted with 0-3 R9d,
aryl substituted with 0-5 R9d, and
5-6 membered heterocyclic group consisting of carbon atoms and 1-4 heteroatoms selected from the group:
O, S, and N, and said heterocyclic group is substituted with 0-4 R9d;
R9d is selected at each occurrence from the group:
H, F, Cl, Br, I, xe2x80x94NO2, xe2x80x94CN, xe2x80x94NCS, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94CH3, xe2x80x94OCH3, xe2x95x90O, OH, xe2x80x94CO2H, phenyl, xe2x80x94NH2, xe2x80x94NH(CH3), xe2x80x94N(CH3)2, xe2x80x94CO2R11, xe2x80x94C(xe2x95x90O)NR11R11, xe2x80x94NHC(xe2x95x90O)R11, xe2x80x94NR11R11, OR11a, xe2x80x94SR11a, xe2x80x94C(xe2x95x90O)R11a, xe2x80x94S(xe2x95x90O)R11a, xe2x80x94SO2R11, xe2x80x94SO2NR11R11, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy;
R10 is selected from the group: xe2x80x94CO2R11, xe2x80x94NR11R11, and C1-C6 alkyl substituted with 0-1 R10a;
R10a is selected from the group: halo, xe2x80x94NO2, xe2x80x94CN, xe2x80x94CF3, xe2x80x94CO2R11, xe2x80x94NR11R11, xe2x80x94OR11, xe2x80x94SR11, xe2x80x94C(xe2x95x90NH)NH2, and aryl substituted with 0-1 R10b;
R10b is selected from the group: xe2x80x94CO2H, xe2x80x94NH2, xe2x80x94OH, xe2x80x94SH, and xe2x80x94C(xe2x95x90NH)NH2;
R10c is H or C1-C4 alkyl;
alternatively, R10 and R10c can be combined to form a C3-C6 cycloalkyl group substituted with 0-1 R10a;
R11 is, at each occurrence, independently H or C1-C4 alkyl;
R11a is, at each occurrence, independently H, C1-C4 alkyl, aryl, or C1-C4 haloalkyl;
R12 is H or C1-C4 alkyl;
R13 is H, methyl, ethyl, propyl, or butyl;
A4, A5, A7, A8, and A9 are independently selected from an amino acid residue;
an amino acid residue, at each occurence, independently comprises a natural amino acid, a modified amino acid or an unnatural amino acid wherein said natural, modified or unnatural amino acid is of either D or L configuration;
R19 is C1-C4 alkyl, C1-C4 haloalkyl, aryl, aryl(C1-C4 alkyl), C3-C6 cycloalkyl, or C3-C6 cycloalkyl(C1-C4 alkyl); R20 is H, C1-C4 alkyl, C1-C4 haloalkyl, aryl, aryl(C1-C4 alkyl)- , C3-C6 cycloalkyl, or C3-C6 cycloalkyl(C1-C4 alkyl)-;
R28 and R29, are independently selected from: H, C1-C4 alkyl, aryl(C1-C4 alkyl)-, and C3-C7 cycloalkyl;
t is 1, 2, or 3; and
q is 0, 1 or 2.
[4] In a further more preferred embodiment, the present invention provide a novel compound of Formula (Ia): wherein
A3 is selected from xe2x80x94R9, xe2x80x94A4xe2x80x94R9, and xe2x80x94A4xe2x80x94A5xe2x80x94R9; and
W is xe2x80x94B(OR26)(OR27), xe2x80x94C(xe2x95x90O)C(xe2x95x90O)NHxe2x80x94Q, xe2x80x94C(xe2x95x90O)CF2C(xe2x95x90O)NHxe2x80x94Q, xe2x80x94C(xe2x95x90O)CF3, xe2x80x94C(xe2x95x90O)H, or an amino acid residue.
[5] In an even more preferred embodiment, the present invention provide a novel compound of Formula (II): 
or a stereoisomer or pharmaceutically acceptable salt form thereof, wherein:
A3 is selected from xe2x80x94R9, xe2x80x94A4xe2x80x94R9, and xe2x80x94A4xe2x80x94A5xe2x80x94R9;
OR26 and OR27 are independently selected from:
a) xe2x80x94OH,
b) xe2x80x94F,
c) xe2x80x94NR28R29,
d) C1-C8 alkoxy, or
when taken together, OR26 and OR27 form:
e) a cyclic boron ester where said chain or ring contains from 2 to 20 carbon atoms, and, optionally, 1, 2, or 3 heteroatoms which can be N, S, or O,
f) a cyclic boron amide where said chain or ring contains from 2 to 20 carbon atoms and, optionally, 1, 2, or 3 heteroatoms which can be N, S, or O,
g) a cyclic boron amide-ester where said chain or ring contains from 2 to 20 carbon atoms and, optionally, 1, 2, or 3 heteroatoms which can be N, S, or O;
R1 1is selected from the group:
H, F,
C1-C6 alkyl substituted with 0-3 R1a,
C2-C6 alkenyl substituted with 0-3 R1a,
C2-C6 alkynyl substituted with 0-3 R1a,
aryl substituted with 0-5 R1a, and
C3-C6 cycloalkyl substituted with 0-3 R1a;
R1a is selected at each occurrence from the group:
Cl, F, Br, I, CF3, CHF2, OH, xe2x95x90O, SH,
xe2x80x94CO2R1b, xe2x80x94SO2R1b, xe2x80x94SO3R1b, xe2x80x94P(O)2R1b, xe2x80x94P(O)3R1b,
xe2x80x94C(xe2x95x90O)NHR1b, xe2x80x94NHC(xe2x95x90O)R1b, xe2x80x94SO2NHR1b, xe2x80x94OR1b, xe2x80x94SR1b, C1-C3 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, xe2x80x94Sxe2x80x94(C1-C6 alkyl),
aryl substituted with 0-5 R1c,
xe2x80x94Oxe2x80x94(CH2)q-aryl substituted with 0-5 R1c,
xe2x80x94Sxe2x80x94(CH2)q-aryl substituted with 0-5 R1c,
5-10 membered heterocyclic group consisting of carbon atoms and 1-4 heteroatoms selected from the group:
O, S, and N, and substituted with 0-3 R1c;
R1b is H,
C1-C4 alkyl substituted with 0-3 R1c,
C2-C4 alkenyl substituted with 0-3 R1c,
C2-C4 alkynyl substituted with 0-3 R1c,
C3-C6 cycloalkyl substituted with 0-5 R1c,
C3-C6 carbocyle substituted with 0-5 R1c,
aryl substituted with 0-5 R1c,
5-6 membered heterocyclic group consisting of carbon atoms and 1-4 heteroatoms selected from the group:
O, S, and N, said heterocyclic group substituted with 0-4 R1c;
R1c is selected at each occurrence from the group:
C1-C4 alkyl, Cl, F, Br, I, OH, C1-C4 alkoxy, xe2x80x94CN, xe2x80x94NO2, xe2x80x94OR1d, xe2x80x94C(xe2x95x90O)OR1d, NR1dR1d, CF3, OCF3, and aryl substituted by 0-3 R1e;
R1d is H, methyl, ethyl, propyl, butyl, phenyl, or benzyl;
R1e is selected at each occurrence from the methyl, ethyl, Cl, F, Br, I, OH, methoxy, ethoxy, xe2x80x94CN, xe2x80x94NO2, xe2x80x94C(xe2x95x90O)OR1d, NR1dR1d, CF3, and OCF3;
R2 is H, methyl, ethyl, propyl, butyl, or cyclopropyl;
R3 is xe2x80x94R4, xe2x80x94NR4R5, xe2x80x94OR4, or xe2x80x94SR4;
R4 is selected from the group:
H,
C1-C8 alkyl substituted with 0-3 R4a,
C2-C8 alkenyl substituted with 0-3 R4a,
C2-C8 alkynyl substituted with 0-3 R4a,
C3-C10 cycloalkyl substituted with 0-4 R4b,
aryl substituted with 0-5 R4b,
5-10 membered heterocyclic group consisting of carbon atoms and 1-4 heteroatoms selected from the group:
O, S, and N, and said heterocyclic group is substituted with 0-3 R4b;
R4a is, at each occurrence, independently selected from:
H, F, Cl, Br, I, xe2x80x94NO2, xe2x80x94CN, xe2x80x94NCS, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94CH3, xe2x80x94OCH3, xe2x95x90O, OH, xe2x80x94CO2H, phenyl, xe2x80x94C(xe2x95x90NH)NH2, xe2x80x94NH2, xe2x80x94NH(CH3), xe2x80x94N(CH3)2,
xe2x80x94CO2R11, xe2x80x94C(xe2x95x90O)NR11R11, xe2x80x94NHC(xe2x95x90O)R11, xe2x80x94NR11R11, xe2x80x94OR11a, xe2x80x94SR11a, xe2x80x94C(xe2x95x90O)R11a, xe2x80x94S(xe2x95x90O)R11a, xe2x80x94SO2R11, xe2x80x94SO2NR11R11, C1-C4 haloalkyl, C1-C4 haloalkoxy,
C3-C10 cycloalkyl substituted with 0-4 R4b,
aryl substituted with 0-5 R4b, and
5-10 membered heterocyclic group consisting of carbon atoms and 1-4 heteroatoms selected from the group:
O, S, and N, and said heterocyclic group is substituted with 0-3 R4b;
R4b is, at each occurrence, independently selected from:
H, F, Cl, Br, I, xe2x80x94NO2, xe2x80x94CN, xe2x80x94NCS, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94CH3, xe2x80x94OCH3, xe2x95x90O, OH, xe2x80x94CO2H, phenyl, xe2x80x94C(xe2x95x90NH)NH2, xe2x80x94NH2, xe2x80x94NH(CH3), xe2x80x94N(CH3)2,
xe2x80x94CO2R11, xe2x80x94C(xe2x95x90O)NR11R11, xe2x80x94NHC(xe2x95x90O)R11, xe2x80x94NR11R11, OR11a, SR11a, C(xe2x95x90O)R11a, S(xe2x95x90O)R11a, xe2x80x94SO2R11, xe2x80x94SO2NR11R11, C1-C4 haloalkyl, C1-C4 haloalkoxy,
C1-C6 alkyl substituted with 0-3 R4c,
C2-C6 alkenyl substituted with 0-3 R4c,
C2-C6 alkynyl substituted with 0-3 R4c,
C3-C6 cycloalkyl substituted with 0-4 R4d,
aryl substituted with 0-5 R4d, and
5-10 membered heterocyclic group consisting of carbon atoms and 1-4 heteroatoms selected from the group:
O, S, and N, and said heterocyclic group is substituted with 0-3 R4d;
R4c is, at each occurrence, independently selected from:
H, F, Cl, Br, I, xe2x80x94NO2, xe2x80x94CN, xe2x80x94NCS, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94CH3, xe2x80x94OCH3, xe2x95x90O, OH, xe2x80x94CO2H, phenyl, xe2x80x94C(xe2x95x90NH)NH2, xe2x80x94NH2, xe2x80x94NH(CH3), xe2x80x94N(CH3)2,
xe2x80x94CO2R11, xe2x80x94C(xe2x95x90O)NR11R11, xe2x80x94NHC(xe2x95x90O)R11, xe2x80x94NR11R11, xe2x80x94OR11a, xe2x80x94SR11a, xe2x80x94C(xe2x95x90O)R11a, xe2x80x94S(xe2x95x90O)R11a, xe2x80x94SO2R11, xe2x80x94SO2NR11R11, C1-C4 haloalkyl, C1-C4 haloalkoxy,
C3-C6 cycloalkyl substituted with 0-4 R4d,
aryl substituted with 0-5 R4d,
5-10 membered heterocyclic group consisting of carbon atoms and 1-4 heteroatoms selected from the group:
O, S, and N, and said heterocyclic group is substituted with 0-3 R4d;
R4d is, at each occurrence, independently selected from:
H, F, Cl, Br, I, xe2x80x94NO2, xe2x80x94CN, xe2x80x94NCS, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94CH3, xe2x80x94OCH3, xe2x95x90O, OH, xe2x80x94CO2H, phenyl, xe2x80x94NH2, xe2x80x94NH(CH3), xe2x80x94N(CH3)2, xe2x80x94CO2R11, xe2x80x94C(xe2x95x90O)NR11R11, xe2x80x94NHC(xe2x95x90O)R11, xe2x80x94NR11R11, xe2x80x94OR11a, xe2x80x94SR11a, xe2x80x94C(xe2x95x90O)R11a, xe2x80x94S(xe2x95x90O)R11a, xe2x80x94SO2R11, xe2x80x94SO2NR11R11, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy;
R5 is selected from the group: H, C1-C6 alkyl, phenyl, phenylmethyl-, phenylethyl-, C3-C6 cycloalkyl, C3-C6 cycloalkylmethyl-, and C3-C6 cycloalkylethyl-;
R6 is H, Cl, Br, methyl, ethyl, or cyclopropyl;
R8 is H, methyl, ethyl, propyl, butyl, or cyclopropyl;
R9 is selected from the group: xe2x80x94S(xe2x95x90O)R9a, xe2x80x94S(xe2x95x90O)2R9a, xe2x80x94C(xe2x95x90O)R9a, xe2x80x94C(xe2x95x90O)OR9a, xe2x80x94C(xe2x95x90O)NHR9a, C1-C3 alkyl-R9a, C2-C6 alkenyl-R9a, and C2-C6 alkynyl-R9a;
R9a is selected from the group: H
C1-C6 alkyl substituted with 0-3 R9b,
C3-C6 cycloalkyl substituted with 0-3 R9c0 and
aryl substituted with 0-3 R9c and
5-14 membered heterocyclic group consisting of carbon atoms and 1-4 heteroatoms selected from the group:
O, S, and N, and said heterocyclic group is substituted with 0-3 R9c;
R9b is selected from the group:
phenyl substituted with 0-3 R9c,
naphthyl substituted with 0-3 R9c,
benzyl substituted with 0-3 R9c, and
5-10 membered heterocyclic group consisting of carbon atoms and 1-4 heteroatoms selected from the group:
O, S, and N; and said heterocyclic group is substituted with 0-3 R9c;
R9c is selected at each occurrence from the group:
H, F, Cl, Br, I, xe2x80x94NO2, xe2x80x94CN, xe2x80x94NCS, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94CH3, xe2x80x94OCH3, xe2x95x90O, OH, xe2x80x94CO2H, phenyl, xe2x80x94NH2, xe2x80x94NH(CH3), xe2x80x94N(CH3)2, xe2x80x94CO2R11, xe2x80x94C(xe2x95x90O)NR11R11, xe2x80x94NHC(xe2x95x90O)R11, xe2x80x94NR11R11, xe2x80x94OR11a, xe2x80x94SR11a, xe2x80x94C(xe2x95x90O)R11a, xe2x80x94S(xe2x95x90O)R11a, xe2x80x94SO2R11, xe2x80x94SO2NR11R11, C1-C4 haloalkyl, C1-C4 haloalkoxy,
C1-C4 alkyl substituted with 0-3 R9d,
C1-C4 alkoxy substituted with 0-3 R9d,
C3-C6 cycloalkyl substituted with 0-3 R9d,
aryl substituted with 0-5 R9d, and
5-6 membered heterocyclic group consisting of carbon atoms and 1-4 heteroatoms selected from the group:
O, S, and N, and said heterocyclic group is substituted with 0-4 R9d;
R9d is selected at each occurrence from the group:
H, F, Cl, Br, I, xe2x80x94NO2, xe2x80x94CN, xe2x80x94NCS, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94CH3, xe2x80x94OCH3, xe2x95x90O, OH, xe2x80x94CO2H, phenyl, xe2x80x94NH2, xe2x80x94NH(CH3), xe2x80x94N(CH3)2, xe2x80x94CO2R11, xe2x80x94C(xe2x95x90O)NR11R11, xe2x80x94NHC(xe2x95x90O)R11, xe2x80x94NR11R11, OR11a, xe2x80x94SR11a, xe2x80x94C(xe2x95x90O)R11a, S(xe2x95x90O)R11a, xe2x80x94SO2R11, xe2x80x94SO2NR11R11, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy;
R11 is, at each occurrence, independently H or C1-C4 alkyl;
R11a is, at each occurrence, independently H, C1-C4 alkyl, aryl, or C1-C4 haloalkyl;
R13 is H, methyl, ethyl, propyl, or butyl;
A4 and A5 are independently selected from an amino acid residue;
an amino acid residue, at each occurence, independently comprises Ala, Arg, Asn, Asp, Aze, Cha, Cys, Dpa, Gln, Glu, Gly, His, Hyp, Ile, Irg, Leu, Lys, Met, Orn, Phe, Phe(4-fluoro), Pro, Sar, Ser, Thr, Trp, Tyr, or Val;
R28 and R29 are independently selected from:
H, methyl, ethyl, propyl, butyl, phenylmethyl-, phenylethyl-, phenylpropyl-, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl;
q is 0, 1 or 2.
[6] In a further even more preferred embodiment, the present invention provides a novel compound of Formula (II): 
or a stereoisomer or pharmaceutically acceptable salt form thereof, wherein:
A3 is xe2x80x94R9 or xe2x80x94A4xe2x80x94R9;
OR26 and OR27 are independently selected from:
a) xe2x80x94OH,
b) xe2x80x94F,
c) C1-C6 alkoxy, or
when taken together, OR26 and OR27 form:
d) a cyclic boron ester where said chain or ring contains from 2 to 16 carbon atoms, and, optionally, 1, 2, or 3 heteroatoms which can be N, S, or O,
R1 is selected from the group: H, F,
C1-C6 alkyl substituted with 0-3 R1a,
C2-C6 alkenyl substituted with 0-3 R1a,
C2-C6 alkynyl substituted with 0-3 R1a, and
C3-C6 cycloalkyl substituted with 0-3 R1a;
R1a is selected at each occurrence from the group:
Cl, F, Br, I, CF3, CHF2, OH, xe2x95x90O, SH, xe2x80x94CO2R1b, xe2x80x94SO2R1b, xe2x80x94SO3R1b, xe2x80x94P(O)2R1b, xe2x80x94P(O )3R1b, xe2x80x94C(xe2x95x90O)NHR1b, xe2x80x94NHC(xe2x95x90O)R1b, xe2x80x94SO2NHR1b, xe2x80x94OR1b, xe2x80x94SR1b, C1-C3 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, xe2x80x94Sxe2x80x94(C1-C6 alkyl),
aryl substituted with 0-5 R1c,
xe2x80x94Oxe2x80x94(CH2)q-aryl substituted with 0-5 R1c,
xe2x80x94Sxe2x80x94(CH2)q-aryl substituted with 0-5 R1c,
5-10 membered heterocyclic group consisting of carbon atoms and 1-4 heteroatoms selected from the group:
O, S, and N, and substituted with 0-3 R1c;
R1b is H,
C1-C4 alkyl substituted with 0-3 R1c,
C2-C4 alkenyl substituted with 0-3 R1c,
C2-C4 alkynyl substituted with 0-3 R1c,
C3-C6 cycloalkyl substituted with 0-5 R1c,
C3-C6 carbocyle substituted with 0-5 R1c,
aryl substituted with 0-5 R1c,
5-6 membered heterocyclic group consisting of carbon atoms and 1-4 heteroatoms selected from the group:
O, S, and N, said heterocyclic group substituted with 0-4 R1c;
R1c is selected at each occurrence from the group:
C1-C4 alkyl, Cl, F, Br, I, OH, C1-C4 alkoxy, xe2x80x94CN, xe2x80x94NO2,
OR1d, xe2x80x94C(xe2x95x90O)OR1d, NR1dR1d, CF3, OCF3, and phenyl substituted with 0-3 R1e;
R1d is H, methyl, ethyl, propyl, butyl, phenyl, or benzyl;
R1e is selected at each occurrence from the methyl, ethyl, Cl, F, Br, I, OH, methoxy, ethoxy, xe2x80x94CN, xe2x80x94NO2, xe2x80x94C(xe2x95x90O)OR1d, NR1dR1d, CF3, and OCF3;
R2 is H, methyl, ethyl, propyl, butyl, or cyclopropyl;
R3 is xe2x80x94R4, xe2x80x94NR4R5, xe2x80x94OR4, or xe2x80x94SR4;
R4 is selected from the group: H,
C1-C6 alkyl substituted with 0-3 R4a,
C2-C6 alkenyl substituted with 0-3 R4a,
C2-C6 alkynyl substituted with 0-3 R4a,
C3-C10 cycloalkyl substituted with 0-4 R4b,
aryl substituted with 0-5 R4b,
5-10 membered heterocyclic group consisting of carbon atoms and 1-4 heteroatoms selected from the group:
O, S, and N, and said heterocyclic group is substituted with 0-3 R4b;
R4a is, at each occurrence, independently selected from:
H, F, Cl, Br, I, xe2x80x94NO2, xe2x80x94CN, xe2x80x94NCS, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94CH3, xe2x80x94OCH3, xe2x95x90O, OH, xe2x80x94CO2H, phenyl, xe2x80x94C(xe2x95x90NH)NH2, xe2x80x94NH2, xe2x80x94NH(CH3), xe2x80x94N(CH3)2,
xe2x80x94CO2R11, xe2x80x94C(xe2x95x90O)NR11R11, xe2x80x94NHC(xe2x95x90O)R11, xe2x80x94NR11R11, OR11a, xe2x80x94SR11a, xe2x80x94C(xe2x95x90O)R11a, xe2x80x94S(xe2x95x90O)R11a, xe2x80x94SO2R11xe2x80x94SO2NR11R11, C1-C4 haloalkyl, C1-C4 haloalkoxy,
C3-C10 cycloalkyl substituted with 0-4 R4b,
aryl substituted with 0-5 R4b, and
5-10 membered heterocyclic group consisting of carbon atoms and 1-4 heteroatoms selected from the group:
O, S, and N, and said heterocyclic group is substituted with 0-3 R4b;
R4b is, at each occurrence, independently selected from:
H, F, Cl, Br, I, xe2x80x94NO2, xe2x80x94CN, xe2x80x94NCS, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94CH3, xe2x80x94OCH3, xe2x95x90O, OH, xe2x80x94CO2H, phenyl, xe2x80x94C(xe2x95x90NH)NH2, xe2x80x94NH2, xe2x80x94NH(CH3), xe2x80x94N(CH3)2,
xe2x80x94CO2R11, xe2x80x94C(xe2x95x90O)NR11R11, xe2x80x94NHC(xe2x95x90O)R11, xe2x80x94NR11R11, OR11a,
xe2x80x94SR11a, xe2x80x94C(xe2x95x90O)R11a, S(xe2x95x90O)R11a, xe2x80x94SO2R11, xe2x80x94SO2NR11R11,
C1-C4 haloalkyl, C1-C4 haloalkoxy,
C1-C6 alkyl substituted with 0-3 R4c,
C2-C6 alkenyl substituted with 0-3 R4c,
C2-C6 alkynyl substituted with 0-3 R4c,
C3-C6 cycloalkyl substituted with 0-4 R4d,
aryl substituted with 0-5 R4d, and
5-6 membered heterocyclic group consisting of carbon atoms and 1-4 heteroatoms selected from the group:
O, S, and N, and said heterocyclic group is substituted with 0-3 R4d;
R4c is, at each occurrence, independently selected from:
H, F, Cl, Br, I, xe2x80x94NO2, xe2x80x94CN, xe2x80x94NCS, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94CH3, xe2x80x94OCH3, xe2x95x90O, OH, xe2x80x94CO2H, phenyl, xe2x80x94C(xe2x95x90NH)NH2, xe2x80x94NH2, xe2x80x94NH(CH3), xe2x80x94N(CH3)2,
xe2x80x94CO2R11, xe2x80x94C(xe2x95x90O)NR11R11, xe2x80x94NHC(xe2x95x90O)R11, xe2x80x94NR11R11, xe2x80x94OR11a, xe2x80x94SR11a, xe2x80x94C(xe2x95x90O)R11a, xe2x80x94S(xe2x95x90O)R11a, xe2x80x94SO2R11, xe2x80x94SO2NR11R11, C1-C4 haloalkyl, C1-C4 haloalkoxy,
C3xe2x80x94C6 cycloalkyl substituted with 0-4 R4d,
aryl substituted with 0-5 R4d,
5-6 membered heterocyclic group consisting of carbon atoms and 1-4 heteroatoms selected from the group:
O, S, and N, and said heterocyclic group is substituted with 0-3 R4d;
R4d is, at each occurrence, independently selected from:
H, F, Cl, Br, I, xe2x80x94NO2, xe2x80x94CN, xe2x80x94NCS, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94CH3, xe2x80x94OCH3, xe2x95x90O, OH, xe2x80x94CO2H, phenyl, xe2x80x94NH2, xe2x80x94NH(CH3), xe2x80x94N(CH3)2, xe2x80x94CO2R11, xe2x80x94C(xe2x95x90O)NR11R11, xe2x80x94NHC(xe2x95x90O)R11, xe2x80x94NR11R11, OR11a, xe2x80x94SR11a, xe2x80x94C(xe2x95x90O)R11a, xe2x80x94S(xe2x95x90O)R11a, xe2x80x94SO2R11, xe2x80x94SO2NR11R11, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy;
R5 is selected from the group:
H, methyl, ethyl, propyl, butyl, phenyl, phenylmethyl-, phenylethyl-, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl-, cyclobutylmethyl-, cyclopentylmethyl-, cyclohexylmethyl-, cyclopropylethyl-, cyclobutylethyl-, cyclopentylethyl-, and cyclohexylethyl-;
R6 is H, Cl, Br, or methyl;
R8 is H, methyl, ethyl, or cyclopropyl;
R9 is selected from the group: xe2x80x94S(xe2x95x90O)R9a, xe2x80x94S(xe2x95x90O)2R9a, xe2x80x94C(xe2x95x90O)R9a, xe2x80x94C(xe2x95x90O)OR9a, xe2x80x94C(xe2x95x90O)NHR9a, C1-C3 alkyl-R9a, C2-C6 alkenyl-R9a, and C2-C6 alkynyl-R9a;
R9a is selected from the group: H
C1-C6 alkyl substituted with 0-3 R9b,
C3-C6 cycloalkyl substituted with 0-3 R9c and
aryl substituted with 0-3 R9c and
5-14 membered heterocyclic group consisting of carbon atoms and 1-4 heteroatoms selected from the group:
O, S, and N, and said heterocyclic group is substituted with 0-3 R9c;
R9c is selected from the group:
phenyl substituted with 0-3 R9c,
naphthyl substituted with 0-3 R9c,
benzyl substituted with 0-3 R9c, and
5-10 membered heterocyclic group consisting of carbon atoms and 1-4 heteroatoms selected from the group:
O, S, and N; and said heterocyclic group is substituted with 0-3 R9c;
R9c is selected at each occurrence from the group:
H, F, Cl, Br, I, xe2x80x94NO2, xe2x80x94CN, xe2x80x94NCS, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94CH3, xe2x80x94OCH3, xe2x95x90O, OH, xe2x80x94CO2H, phenyl, xe2x80x94NH2, xe2x80x94NH(CH3), xe2x80x94N(CH3)2, xe2x80x94CO2R11, xe2x80x94C(xe2x95x90O)NR11R11, xe2x80x94NHC(xe2x95x90O)R11, xe2x80x94NR11R11, OR11a, xe2x80x94SR11a, xe2x80x94C(xe2x95x90O)R11a, xe2x80x94S(xe2x95x90O)R11a, xe2x80x94SO2R11, xe2x80x94SO2NR11R11, C1-C4 haloalkyl, C1-C4 haloalkoxy,
C1-C4 alkyl substituted with 0-3 R9d,
C1-C4 alkoxy substituted with 0-3 R9d,
C3-C6 cycloalkyl substituted with 0-3 R9d,
aryl substituted with 0-5 R9d, and
5-6 membered heterocyclic group consisting of carbon atoms and 1-4 heteroatoms selected from the group:
O, S, and N, and said heterocyclic group is substituted with 0-4 R9d;
R9d is selected at each occurrence from the group:
H, F, Cl, Br, I, xe2x80x94NO2, xe2x80x94CN, xe2x80x94NCS, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94CH3, xe2x80x94OCH3, xe2x95x90O, OH, xe2x80x94CO2H, phenyl, xe2x80x94NH2, xe2x80x94NH(CH3), xe2x80x94N(CH3)2, xe2x80x94CO2R11, xe2x80x94C(xe2x95x90O)NR11R11, xe2x80x94NHC(xe2x95x90O)R11, xe2x80x94NR11R11, xe2x80x94OR11a, xe2x80x94SR11a, C(xe2x95x90O)R11a, S(xe2x95x90O)R11a, xe2x80x94SO2R11, xe2x80x94SO2NR11R11, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy;
R11 is, at each occurrence, independently H or C1-C4 alkyl;
R11a is, at each occurrence, independently H, C1-C4 alkyl, aryl, or C1-C4 haloalkyl;
R13 is H, methyl, ethyl, propyl, or butyl;
A4 is selected from Ala, Arg, Asn, Asp, Aze, Cha, Cys, Dpa, Gln, Glu, Gly, His, Hyp, Ile, Irg, Leu, Lys, Met, Orn, Phe, Phe(4-fluoro), Pro, Sar, Ser, Thr, Trp, Tyr, or Val; and
q is 0, 1 or 2.
[7] In most preferred embodiment, the present invention provides a compound of Formula (II): 
or a stereoisomer or pharmaceutically acceptable salt form thereof, wherein:
A3 is xe2x80x94R9;
OR26 and OR27 are independently selected from:
a) xe2x80x94OH,
b) xe2x80x94F,
c) methyloxy, ethyloxy, propyloxy, butyloxy, pentyloxy, or hexyloxy,
when taken together, OR26 and OR27 form:
d) a cyclic boron ester where said chain or ring contains from 2 to 12 carbon atoms, and, optionally, a heteroatom which can be N, S, or O;
R1 is selected from the group: H, F,
C1-C6 alkyl substituted with 0-3 R1a,
C2-C6 alkenyl substituted with 0-3 R1a,
C2-C6 alkynyl substituted with 0-3 R1a, and
C3-C6 cycloalkyl substituted with 0-3 R1a;
R1a is selected at each occurrence from the group:
Cl, F, Br, I, CF3, CHF2, OH, xe2x95x90O, SH, xe2x80x94CO2R1b, xe2x80x94SO2R1b, xe2x80x94SO3R1b, xe2x80x94P(O)2R1b, xe2x80x94P(O)3R1b, xe2x80x94C(xe2x95x90O)NHR1b, xe2x80x94NHC(xe2x95x90O)R1b, xe2x80x94SO2NHR1b, xe2x80x94OR1b, xe2x80x94SR1b, C1-C3 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy,
aryl substituted with 0-5 R1c,
5-6 membered heterocyclic group consisting of carbon atoms and 1-4 heteroatoms selected from the group:
pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, pyrazinyl, piperazinyl, piperidinyl, imidazolyl, imidazolidinyl, indolyl, tetrazolyl, isoxazolyl, morpholinyl, oxazolyl, oxazolidinyl, tetrahydrofuranyl, thiadiazinyl, thiadiazolyl, thiazolyl, triazinyl, and triazolyl; said heterocyclic group substituted with 0-3 R1c;
R1b is H,
C1-C4 alkyl substituted with 0-3 R1c,
C2-C4 alkenyl substituted with 0-3 R1c,
C2-C4 alkynyl substituted with 0-3 R1c,
C3-C6 cycloalkyl substituted with 0-5 R1c,
C3-C6 carbocyle substituted with 0-5 R1c,
aryl substituted with 0-5 R1c,
5-6 membered heterocyclic group consisting of carbon atoms and 1-4 heteroatoms selected from the group:
pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, pyrazinyl, piperazinyl, piperidinyl, imidazolyl, imidazolidinyl, indolyl, tetrazolyl, isoxazolyl, morpholinyl, oxazolyl, oxazolidinyl, tetrahydrofuranyl, thiadiazinyl, thiadiazolyl, thiazolyl, triazinyl, and triazolyl; said heterocyclic group substituted with 0-3 R1c;
R1c is selected at each occurrence from the group:
C1-C4 alkyl, Cl, F, Br, I, OH, C1-C4 alkoxy, xe2x80x94CN, xe2x80x94NO2, xe2x80x94OR1d, C(xe2x95x90O)OR1d, NR1dR1d, CF3, OCF3, and phenyl substituted with 0-3 R1e;
R1d is H, methyl, ethyl, propyl, butyl or phenyl;
R1e is selected at each occurrence from the group:
methyl, ethyl, Cl, F, Br, I, OH, methoxy, ethoxy, xe2x80x94CN, xe2x80x94NO2, xe2x80x94C (xe2x95x90O)OR1d, NR1dR1d, CF3, and OCF3;
R2 is H;
R3 is xe2x80x94R4 or xe2x80x94R4;
R4 is selected from the group: H,
C1-C4 alkyl substituted with 0-3 R4a,
C2-C4 alkenyl substituted with 0-3 R4a,
C2-C4 alkynyl substituted with 0-3 R4a,
C3-C6 substituted with 0-4 R4b,
aryl substituted with 0-5 R4b,
5-6 membered heterocyclic group consisting of carbon atoms and 1-4 heteroatoms selected from the group:
pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, pyrazinyl, piperazinyl, piperidinyl, imidazolyl, imidazolidinyl, indolyl, tetrazolyl, isoxazolyl, morpholinyl, oxazolyl, oxazolidinyl, tetrahydrofuranyl, thiadiazinyl, thiadiazolyl, thiazolyl, triazinyl, and triazolyl; said heterocyclic group substituted with 0-3 R4b;
R4a is, at each occurrence, independently selected from:
H, F, Cl, Br, I, xe2x80x94NO2, xe2x80x94CN, xe2x80x94NCS, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94CH3, xe2x80x94OCH3, xe2x95x90OH, xe2x80x94CO2H, phenyl, xe2x80x94C(xe2x95x90NH)NH2, xe2x80x94NH2, xe2x80x94NH(CH3), xe2x80x94N(CH3)2, xe2x80x94CO2R11, xe2x80x94C(xe2x95x90O)NR11R11, xe2x80x94NHC(xe2x95x90O)R11, xe2x80x94NR11R11, xe2x80x94OR11a, xe2x80x94SR11a, xe2x80x94C(xe2x95x90O)R11a, xe2x80x94S(xe2x95x90O)R11a, xe2x80x94SO2R11, xe2x80x94SO2NR11R11, C1-C4 haloalkyl, C1-C4 haloalkoxy,
C3-C6 cycloalkyl substituted with 0-4 R4b,
aryl substituted with 0-5 R4b, and
5-6 membered heterocyclic group consisting of carbon atoms and 1-4 heteroatoms selected from the group:
pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, pyrazinyl, piperazinyl, piperidinyl, imidazolyl, imidazolidinyl, indolyl, tetrazolyl, isoxazolyl, morpholinyl, oxazolyl, oxazolidinyl, tetrahydrofuranyl, thiadiazinyl, thiadiazolyl, thiazolyl, triazinyl, and triazolyl; said heterocyclic group substituted with 0-3 R4b;
R4b is, at each occurrence, independently selected from:
H, F, Cl, Br, I, xe2x80x94NO2, xe2x80x94CN, xe2x80x94NCS, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94CH3, xe2x80x94OCH3, xe2x95x90O, OH, xe2x80x94CO2H, phenyl, xe2x80x94C(xe2x95x90NH)NH2, xe2x80x94NH2, xe2x80x94NH(CH3), xe2x80x94N(CH3)2,
xe2x80x94CO2R11, xe2x80x94C(xe2x95x90O)NR11R11, xe2x80x94NHC(xe2x95x90O)R11, xe2x80x94NR11R11, xe2x80x94OR11a, xe2x80x94SR11a, xe2x80x94C(xe2x95x90O)R11a, xe2x80x94S(xe2x95x90O)R11a, xe2x80x94SO2R11, xe2x80x94SO2NR11R11, C1-C4 haloalkyl, C1-C4 haloalkoxy,
C1-C4 alkyl substituted with 0-3 R4c,
C2-C4 alkenyl substituted with 0-3 R4c,
C2-C4 alkynyl substituted with 0-3 R4c,
C3-C6 cycloalkyl substituted with 0-4 R4d,
aryl substituted with 0-5 R4d, and
5-6 membered heterocyclic group consisting of carbon atoms and 1-4 heteroatoms selected from the group:
pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, pyrazinyl, piperazinyl, piperidinyl, imidazolyl, imidazolidinyl, indolyl, tetrazolyl, isoxazolyl, morpholinyl, oxazolyl, oxazolidinyl, tetrahydrofuranyl, thiadiazinyl, thiadiazolyl, thiazolyl, triazinyl, and triazolyl; said heterocyclic group substituted with 0-3 R4d;
R4c is, at each occurrence, independently selected from:
H, F, Cl, Br, I, xe2x80x94NO2, xe2x80x94CN, xe2x80x94NCS, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94CH3, xe2x80x94OCH3, xe2x95x90O, OH, xe2x80x94CO2H, phenyl, xe2x80x94C(xe2x95x90NH)NH2, xe2x80x94NH2, xe2x80x94NH(CH3), xe2x80x94N(CH3)2,
xe2x80x94CO2R11, xe2x80x94C(xe2x95x90O)NR11R11, xe2x80x94NHC(xe2x95x90O)R11, xe2x80x94NR11R11, OR11a, xe2x80x94SR11a, xe2x80x94C(xe2x95x90O)R11a, xe2x80x94S(xe2x95x90O)R11a, xe2x80x94SO2R11, xe2x80x94SO2NR11R11, C1-C4 haloalkyl, C1-C4 haloalkoxy,
C3-C6 cycloalkyl substituted with 0-4 R4d,
aryl substituted with 0-5 R4d,
5-6 membered heterocyclic group consisting of carbon atoms and 1-4 heteroatoms selected from the group:
pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, pyrazinyl, piperazinyl, piperidinyl, imidazolyl, imidazolidinyl, indolyl, tetrazolyl, isoxazolyl, morpholinyl, oxazolyl, oxazolidinyl, tetrahydrofuranyl, thiadiazinyl, thiadiazolyl, thiazolyl, triazinyl, and triazolyl; said heterocyclic group substituted with 0-3 R4d;
R4d is, at each occurrence, independently selected from:
H, F, Cl, Br, I, xe2x80x94NO2, xe2x80x94CN, xe2x80x94NCS, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94CH3, xe2x80x94OCH3, OH, xe2x80x94CO2H, phenyl, xe2x80x94NH2, xe2x80x94NH(CH3), xe2x80x94N(CH3)2, xe2x80x94CO2R11, xe2x80x94C(xe2x95x90O)NR11R11, xe2x80x94NHC(xe2x95x90O)R11, xe2x80x94NR11R11, OR11a, xe2x80x94SR11a, C(xe2x95x90O)R11a, xe2x80x94S(xe2x95x90O)R11a, xe2x80x94SO2R11, xe2x80x94SO2NR11R11, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy;
R6 is H, Cl or Br;
R8 is H;
R9 is xe2x80x94S(xe2x95x90O)2R9a, xe2x80x94C(xe2x95x90O)R9a, xe2x80x94C(xe2x95x90O)NHR9a, xe2x80x94CH2xe2x80x94R9a,
CH2CH2 xe2x80x94R9 , or xe2x80x94CH2CH2CH2xe2x80x94R9a;
R9a is selected from the group: H
C1-C6 alkyl substituted with 0-3 R9b,
C3-C6 cycloalkyl substituted with 0-3 R9c and
aryl substituted with 0-3 R9c and
5-10 membered heterocyclic group consisting of carbon atoms and 1-4 heteroatoms selected from the group:
pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, pyrazinyl, piperazinyl, piperidinyl, imidazolyl, imidazolidinyl, indolyl, tetrazolyl, isoxazolyl, moripholinyl, oxazolyl, oxazolidinyl, tetrahydrofuranyl, thiadiazinyl, thiadiazolyl, thiazolyl, triazinyl, triazolyl, benzimidazolyl, 1H-indazolyl, benzofuranyl, benzothiofuranyl, benztetrazolyl, benzotriazolyl, benzisoxazolyl, benzoxazolyl, oxindolyl, benzoxazolinyl, benzthiazolyl, benzisothiazolyl, isatinoyl, isoquinolinyl, octahydroisoquinolinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, isoxazolopyridinyl, quinazolinyl, quinolinyl, isothiazolopyridinyl, thiazolopyridinyl, oxazolopyridinyl, imidazolopyridinyl, and pyrazolopyridinyl; and substituted with 0-3 R9c;
R9b is selected from the group:
phenyl substituted with 0-3 R9c,
naphthyl substituted with 0-3 R9c,
benzyl substituted with 0-3 R9c, and
5-10 membered heterocyclic group consisting of carbon atoms and 1-4 heteroatoms selected from the group:
pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, pyrazinyl, piperazinyl, piperidinyl, imidazolyl, imidazolidinyl, indolyl, tetrazolyl, isoxazolyl, morpholinyl, oxazolyl, oxazolidinyl, tetrahydrofuranyl, thiadiazinyl, thiadiazolyl, thiazolyl, triazinyl, triazolyl, benzimidazolyl, 1H-indazolyl, benzofuranyl, benzothiofuranyl, benztetrazolyl, benzotriazolyl, benzisoxazolyl, benzoxazolyl, oxindolyl, benzoxazolinyl, benzthiazolyl, benzisothiazolyl, isatinoyl, isoquinolinyl, octahydroisoquinolinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, isoxazolopyridinyl, quinazolinyl, quinolinyl, isothiazolopyridinyl, thiazolopyridinyl, oxazolopyridinyl, imidazolopyridinyl, and pyrazolopyridinyl; and substituted with 0-3 R9c;
R9c is selected at each occurrence from the group:
H, F, Cl, Br, I, xe2x80x94NO2, xe2x80x94CN, xe2x80x94NCS, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94CH3, xe2x80x94OCH3, xe2x95x90O, OH, xe2x80x94CO2H, phenyl, xe2x80x94NH2, xe2x80x94NH(CH3), xe2x80x94N(CH3)2, xe2x80x94CO2R11, xe2x80x94C(xe2x95x90O)NR11R11, xe2x80x94NHC(xe2x95x90O)R11, xe2x80x94NR11R11, xe2x80x94OR11a, xe2x80x94SR11a, xe2x80x94C(xe2x95x90O)R11a, xe2x80x94S(xe2x95x90O)R11a, xe2x80x94SO2R11, xe2x80x94SO2NR11R11, C1-C4 haloalkyl, C1-C4 haloalkoxy,
C1-C4 alikyl substituted with 0-3 R9d,
C1-C4 alkoxy substituted with 0-3 R9d,
C3-C6 cycloalkyl substituted with 0-3 R9d,
aryl substituted with 0-5 R9d, and
5-6 membered heterocyclic group consisting of carbon atoms and 1-4 heteroatoms selected from the group:
pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, pyrazinyl, piperazinyl, piperidinyl, imidazolyl, imidazolidinyl, indolyl, tetrazolyl, isoxazolyl, morpholinyl, oxazolyl, oxazolidinyl, tetrahydrofuranyl, thiadiazinyl, thiadiazolyl, thiazolyl, triazinyl, and triazolyl; said heterocyclic group substituted with 0-3 R9d;
R9d is selected at each occurrence from the group:
H, F, Cl, Br, I, xe2x80x94NO2, xe2x80x94CN, xe2x80x94NCS, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94CH3, xe2x80x94OCH3, xe2x95x90O, OH, xe2x80x94CO2H, phenyl, xe2x80x94NH2, xe2x80x94NH(CH3), xe2x80x94N(CH3)2, xe2x80x94CO2R11, xe2x80x94C(xe2x95x90O)NR11R11, xe2x80x94NHC(xe2x95x90O)R11, xe2x80x94NR11R11, xe2x80x94OR11a, xe2x80x94SR11a, xe2x80x94C(xe2x95x90O)R11a, xe2x80x94S(xe2x95x90O)R11a, xe2x80x94SO2R11, xe2x80x94SO2NR11R11, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy;
R11 is, at each occurrence, independently H, methyl, ethyl propyl, or butyl;
R11a is, at each occurrence, independently H, methyl, ethyl propyl, butyl, phenyl, naphthyl, or trifluoromethyl;
R13 is H, methyl, ethyl, propyl, or butyl; and
q is 0, 1 or 2.
[8] In a further more preferred embodiment, the present invention provides novel compounds of Formula (IIa): 
or a stereoisomer or pharmaceutically acceptable salt form thereof, wherein:
OR26 and OR27 are independently selected from:
a) xe2x80x94OH,
b) xe2x80x94F,
c) methyloxy, ethyloxy, propyloxy, butyloxy, pentyloxy, or hexyloxy, and
when taken together, OR26 and OR27 form:
d) pinandiol, pinacol, 1,2-ethanediol, 1,2-propanediol, 1,3-propanediol, 2,3-butanediol, 1,2-diisopropylethanediol, 5,6-decanediol, or 1,2-dicyclohexylethanediol;
R1 is selected from the group: xe2x80x94CH2CH3, xe2x80x94CH2CH2CH3, xe2x80x94CH(CH3)2, xe2x80x94CH2CH2CH2CH3, xe2x80x94CH2CH(CH3)2, xe2x80x94CH2C(CH3)3, xe2x80x94CH2CH2C(CH3)3, xe2x80x94CH2CH2CH2C(CH3)3, xe2x80x94CH2CH2CH2CH(CH3)2, xe2x80x94CH2CH2CH2CH(CH2CH3)2, xe2x80x94CH2CH2CH2CH2CH3, xe2x80x94CH2CH2CH(CH3)2, xe2x80x94CH2CH2CH2CH2CH2CH3, xe2x80x94CH2CF3, xe2x80x94CH2CH2CF3, xe2x80x94CH2CH2CH2CF3, xe2x80x94CH2CHF2, xe2x80x94CH2CH2CHF2, xe2x80x94CH2CH2CH2CHF2, xe2x80x94CHxe2x95x90CH2, xe2x80x94CH2CHxe2x95x90CH2, xe2x80x94CHxe2x95x90CHCH3, cisxe2x80x94CH2CHxe2x95x90CH(CH3), trans-CH2CHxe2x95x90CH(CH3), xe2x80x94CH2CH2CHxe2x95x90CH, xe2x80x94CH2CHxe2x95x90C(CH3)2, xe2x80x94CH2CH2CHxe2x95x90C(CH3)2, xe2x80x94CH2CO2H, xe2x80x94CH2CH2CO2H, xe2x80x94CH2CO2C(CH3)3, xe2x80x94CH2CH2CO2C(CH3)3, xe2x80x94CH2CH2CH2CH2NH2, phenyl, benzyl, phenethyl, phenpropyl, phenbutyl, (2-methylphenyl)ethyl-, (3-methylphenyl)ethyl-, (4-methylphenyl)ethyl-, (4-ethylphenyl)ethyl-, (4-i-propylphenyl)ethyl-, (4-t-butylphenyl)ethyl-, (4-hydroxyphenyl)ethyl-, (4-phenyl-phenyl)ethyl-, (4-phenoxy-phenyl)ethyl-, (4-cyclohexyl-phenyl)ethyl -, (4-cyclopropyl-phenyl)ethyl-, (2,5-dimethylphenyl)ethyl-, (2,4-dimethylphenyl)ethyl-, (2,6-difluorophenyl)ethyl-, (4-cyclopentyl-phenyl) ethyl-, (4-cyclobutyl-phenyl)ethyl-, (2-trifluoromethylphenyl)ethyl-, (3-trifluoromethylphenyl)ethyl-, (4-trifluoromethylphenyl)ethyl-, (2-fluorophenyl)ethyl-, (3-fluorophenyl)ethyl-, (4-fluorophenyl)ethyl-, (2-chlorophenyl)ethyl-, (3-chlorophenyl)ethyl-, (4-chlorophenyl)ethyl-, (2-bromophenyl)ethyl-, (3-bromophenyl)ethyl-, (4-bromophenyl)ethyl-, (2,3,4,5,6-pentafluorophenyl)ethyl-(naphth-2-yl)ethyl, (cyclobutyl)methyl, (cyclobutyl)ethyl, (cyclobutyl)propyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl;
R3 is selected from the group: methyl, ethyl, propyl, butyl, pentyl, hexyl, phenylmethyl, phenylethyl, phenylpropyl, (cyclopropyl)methyl, (cyclopropyl)ethyl, (cyclopropyl)propyl, (cyclohexyl)methyl, (cyclohexyl)ethyl, (cyclohexyl)propyl, (3-methylphenyl)methyl-, (4-methylphenyl)methyl-, (3-CF3-phenyl)methyl-, (4-CF3-phenyl)methyl-, (3-methoxyphenyl)methyl-, (4-methoxyphenyl)methyl-, phenylmethyl-O-, phenylethyl-O-, (naphth-1-yl)methyl-O-, and (naphth-2-yl)methyl-O-;
R6 is H or Cl;
R9 is selected from the group: methyl, ethyl, propyl, butyl, pentyl, hexyl, trifluoromethyl, phenylmethyl, phenylethyl, phenylpropyl, (3-phenyl-phenyl)methyl-, (4-phenyl-phenyl)methyl-, (2-methylphenyl)methyl-, (3-methylphenyl)methyl-, (4-methylphenyl)methyl-, (2-fluorophenyl)methyl-, (3-fluorophenyl)methyl-, (4-fluorophenyl)methyl-, (2-chlorophenyl)methyl-, (3-chlorophenyl)methyl-, (4-chlorophenyl)methyl-, (2-bromophenyl)methyl-, (3-bromophenyl)methyl-, (4-bromophenyl)methyl-, (2-cyanophenyl)methyl-, (3-cyanophenyl)methyl-, (4-cyanophenyl)methyl-, (2-nitrophenyl)methyl-, (3-nitrophenyl)methyl-, (4-nitrophenyl)methyl-, (2-aminophenyl)methyl-, (3-aminophenyl)methyl-, (4-aminophenyl)methyl-, (2-CF3SO2-phenyl)methyl-, (3-CF3SO2-phenyl)methyl-, (4-CF3SO2-phenyl)methyl-, (2-CF3-phenyl)methyl-, (3-CF3-phenyl)methyl-, (4-CF3-phenyl)methyl-, (2-methoxyphenyl)methyl-, (3-methoxyphenyl)methyl-, (4-methoxyphenyl)methyl-, (2-CF3O-phenyl)methyl-, (3-CF3O-phenyl)methyl-, (4-CF3O-phenyl)methyl-, (2-CF3S-phenyl)methyl-, (3-CF3S-phenyl)methyl-, (4-CF3S-phenyl)methyl-, (3,5-diCF3-phenyl)methyl-, (3,4-diCF3-phenyl)methyl-, (3,5-diCl-phenyl)methyl-, (2,5-diCl-phenyl)methyl-, (3,4-diCl-phenyl)methyl-, (3,5-diF-phenyl)methyl-, (2,5-diF-phenyl)methyl-, (3,4-diF-phenyl)methyl-, (2-furanyl)methyl-, (3-furanyl)methyl-, (2-pyridyl)methyl-, (3-pyridyl)methyl-, (4-pyridyl)methyl-, (1,3-benzodioxolo-5-yl)methyl-, (cyclopropyl)methyl-, (cyclobutyl)methyl-, (cyclopentyl)methyl-, and (cyclohexyl)methyl-; R11 is, at each occurrence, independently H, methyl, ethyl propyl, or butyl; R11a is, at each occurrence, independently H, methyl, ethyl propyl, butyl, or trifluoromethyl;
R13 is H or methyl; and
q is 0, 1 or 2.
[9] In a more preferred embodiment, the present invention provides a compound selected from the group:
(6S,8R)- N-[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-butenyl]-1-chloro-4,6,7,8-tetrahydro-4-oxo-3-[[[4-methoxyphenyl]methyl]amino]-pyrrolo[1,2-a]pyrazine-6-carboxamide;
(6S,8R)-N-[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-butenyl]-1-chloro-4,6,7,8-tetrahydro-4-oxo-8-(3-phenylpropyl)-3-[[[3-(trifluoromethyl)phenyl]methyl]amino]-pyrrolo[1,2-a]pyrazine-6-carboxamide;
(6S,8R)-N-[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-butenyl]-1-chloro-4,6,7,8-tetrahydro-4-oxo-8-(3-phenylpropyl)-3-[[[2,5-difluorophenyl]methyl]amino]-pyrrolo[1,2-a]pyrazine-6-carboxamide;
(6S,8R)-N-[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-butenyl]-1-chloro-4,6,7,8-tetrahydro-4-oxo-8-(3-phenylpropyl)-3-[[[3-methylphenyl]methyl]amino]-pyrrolo[1,2-a]pyrazine-6-carboxamide;
(6S,8R)-N-[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-butenyl]-1-chloro-4,6,7,8-tetrahydro-4-oxo-8-(3-phenylpropyl)-3-[[[3-(trifluoromethyl)thiophenyl]methyl]-amino]-pyrrolo[1,2-a]pyrazine-6-carboxamide;
(6S,8R)-N-[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-butenyl]-1-chloro-4,6,7,8-tetrahydro-4-oxo-8-(3-phenylpropyl)-3-[[[3,4-difluorophenyl]methyl]amino]-pyrrolo[1,2-a]pyrazine-6-carboxamide;
(6S, 8R)-N-[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-butenyl]-1-chloro-4,6,7,8-tetrahydro-4-oxo-8-(3-phenylpropyl)-3-[[[3,5-bis(trifluoromethyl)phenyl]methyl]-amino]-pyrrolo[1,2-a]pyrazine-6-carboxamide;
(6S,8R)-N-[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-butenyl]-1-chloro-4,6,7,8-tetrahydro-4-oxo-8-(3-phenylpropyl)-3-[[1,3-benzodioxolo-5-methyl]amino]-pyrrolo[1,2-a]pyrazine-6-carboxamide;
(6S, 8R)-N-[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-[2,2-difluoroethyl]]-1-chloro-4,6,7,8-tetrahydro-4-oxo-8-(3-phenylpropyl)-3-[[[3-trifluoromethylphenyl]methyl]amino]-pyrrolo[1,2-a]pyrazine-6-carboxamide;
(6S,8R)-N-[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-butenyl]-1-chloro-4,6,7,8-tetrahydro-4-oxo-8-(3-phenylpropyl)-3-[[[3-biphenyl]methyl]amino]-pyrrolo[1,2-a]pyrazine-6-carboxamide;
(6S,8R)-N-[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-butenyl]-1-chloro-4,6,7,8-tetrahydro-4-oxo-8-(3-phenylpropyl)-3-[[[3-nitro-phenyl]methyl]amino]-pyrrolo[1,2-a]pyrazine-6-carboxamide;
(6S,8R)-N-[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-butenyl]-1-chloro-4,6,7,8-tetrahydro-4-oxo-8-(3-phenylpropyl)-3-[[[2-furanyl]methyl]amino]-pyrrolo[1,2-a]pyrazine-6-carboxamide;
(6S,8R)-N-[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-butenyl]-1-chloro-4,6,7,8-tetrahydro-4-oxo-8-(3-phenylpropyl)-3-[1-hexyl]amino]-pyrrolo(1,2-a]pyrazine-6-carboxamide;
(6S,8R)-N-[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-butenyl]-1-chloro-4,6,7,8-tetrahydro-4-oxo-8-(3-phenylpropyl)-3-[(methyl)amino]-pyrrolo[1,2-a]pyrazine-6-carboxamide;
(6S,8R)-N-[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-butenyl]-1-chloro-4,6,7,8-tetrahydro-4-oxo-8-(3-phenylpropyl)-3-[[phenylmethyl]amino]-pyrrolo(1,2-a]pyrazine-6-carboxamide;
(6S,8R)-N-[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-butenyl]-1-chloro-4,6,7,8-tetrahydro-4-oxo-8-(3-phenylpropyl)-3-[[[3-fluoro-phenyl]methyl]amino]-pyrrolo[1,2-a]pyrazine-6-carboxamide;
(6S,8R)-N-[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-butenyl]-1-chloro-4,6,7,8-tetrahydro-4-oxo-8-(3-phenylpropyl)-3-[[[3-chloro-phenyl]methyl]amino]-pyrrolo[1,2-a]pyrazine-6-carboxamide;
(6S,8R)-N-[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-butenyl]-1-chloro-4,6,7,8-tetrahydro-4-oxo-8-(3-phenylpropyl)-3-[[[3-methoxy-phenyl]methyl]amino]-pyrrolo[1,2-a]pyrazine-6-carboxamide;
(6S,8R)-N-[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-butenyl]-1-chloro-4,6,7,8-tetrahydro-4-oxo-8-(3-phenylpropyl)-3-[[[4-methoxy-phenyl]methyl]amino]-pyrrolo[1,2-a]pyrazine-6-carboxamide;
(6S,8R)-N-[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-butenyl]-1-chloro-4,6,7,8-tetrahydro-4-oxo-8-(3-phenylpropyl)-3-[[[3-cyano-phenyl]methyl]amino]-pyrrolo [1,2-a]-pyrazine-6-carboxamide;
(6S,8R)-N-[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-butenyl]-1-chloro-4,6,7,8-tetrahydro-4-oxo-8-benzyl-3-[[[3-trifluromethyl-phenyl]methyl]amino]-pyrrolo[1, 2-a]pyrazine-6 -carboxamide;
(6S,8R)-N-[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-butenyl]-1-chloro-4,6,7,8-tetrahydro-4-oxo-8-(3-naphthylmethyl)-3-[[[3-trifluromethyl-phenyl]methyl]amino]-pyrrolo[1,2-a]pyrazine-6-carboxamide;
(6S,8R)-N-[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-butenyl]-1-chloro-4,6,7,8-tetrahydro-4-oxo-8-(4-dimethylethylbenzyl)-3-[[[3-trifluromethyl-phenyl]methyl]amino]-pyrrolo[1,2-a]pyrazine-6-carboxamide;
(6S,8R)-N-[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-butenyl]-1-chloro-4,6,7,8-tetrahydro-4-oxo-8-(4-methylbenzyl)-3-[[[3-trifluromethyl-phenyl]methyl]amino]-pyrrolo(1,2-a]pyrazine-6-carboxamide;
(6S,8R)-N-[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-butenyl]-1-chloro-4,6,7,8-tetrahydro-4-oxo-8-(4-trifluoromethylbenzyl)-3-[[[3-trifluromethyl-phenyl]methyl]amino]-pyrrolo[1,2-a]pyrazine-6-carboxamide;
(6S,8R)-N-[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-butenyl]-1-chloro-4,6,7,8-tetrahydro-4-oxo-8-benzyl-3-[[[3-cyano-phenyl]methyl]amino]-pyrrolo[1,2-a]pyrazine-6-carboxamide;
(6S,8R)-N-[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-butenyl]-1-chloro-4,6,7,8-tetrahydro-4-oxo-8-(3-methylbenzyl)-3-[[[3-trifluromethyl-phenyl]methyl]amino]-pyrrolo[1,2-a]pyrazine-6-carboxamide;
(6S,8R)-N-[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-butenyl]-1-chloro-4,6,7,8-tetrahydro-4-oxo-8-(3,5-dimethylbenzyl)-3-(([3-trifluromethyl-phenyl]methyl]amino]-pyrrolo[1,2-a]pyrazine-6-carboxamide;
(6S,8R)-N-[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-butenyl]-1-chloro-4,6,7,8-tetrahydro-4-oxo-8-(3-methoxybenzyl)-3-[[[3-trifluromethyl-phenyl]methyl]amino]-pyrrolo[1,2-a]pyrazine-6-carboxamide;
(6S)-1-chloro-N-[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-butenyl]-4,6,7,8-tetrahydro-8,8-dimethyl-4-oxo-3-[[[3-(trifluoromethyl)phenyl]methyl]amino]pyrrolo[1,2-a]pyrazine-6-carboxamide;
(6S,8R)-1-chloro-N-[(1R)-1-[(3aS,4S,6S,7aR)-Hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-butenyl]-4,6,7,8-tetrahydro-8-methyl-4-oxo-8-(3-phenylpropyl)-3-[[[3-(trifluoromethyl)phenyl]methyl]amino]pyrrolo[1,2-a]pyrazine-6-carboxamide;
(6S,8S)-1-chloro-N-[(1R)-1-[(3aS,4S,6S,7aR)-Hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-butenyl]-4,6,7,8-tetrahydro-8-methyl-4-oxo-8-(3-phenylpropyl)-3-[[[3-(trifluoromethyl)phenyl]methyl]amino]pyrrolo[1,2-a]pyrazine-6-carboxamide;
(6S)-N-[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-butenyl]-4,6,7,8-tetrahydro-8,8-dimethyl-4-oxo-3-[[[3-(trifluoromethyl)phenyl]methyl]amino]pyrrolo[1,2-a]pyrazine-6-carboxamide;
(6S,8R)-N-[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-butenyl]-4,6,7,8-tetrahydro-8-methyl-4-oxo-8-(3-phenylpropyl)-3-[[[3-(trifluoromethyl)phenyl]methyl]amino]pyrrolo[1,2-a]pyrazine-6-carboxamide;
(6S,8S)-N-[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-butenyl]-4,6,7,8-tetrahydro-8-methyl-4-oxo-8-(3-phenylpropyl)-3-[[[3-(trifluoromethyl)phenyl]methyl]amino]pyrrolo[1,2-a]pyrazine-6-carboxamide;
(6S)-1-chloro-N-[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-butenyl]-4,6,7,8-tetrahydro-4-oxo-8,8-di(3-phenylpropyl)-3-[[[3-(trifluoromethyl)phenyl]methyl]amino]pyrrolo[1,2-a]pyrazine-6-carboxamide;
(6S,8R)-N-[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-butenyl]-1-chloro-4,6,7,8-tetrahydro-4-oxo-8-(3-naphthylmethoxy)-3-[[[3-trifluromethyl-phenyl]methyl]amino]-pyrrolo[1,2-a]pyrazine-6-carboxamide;
(6S,8R)-N-[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-(4-trifluoromethylphenylethyl)]-1-chloro-4,6,7,8-tetrahydro-4-oxo-8-(3-methoxybenzyl)-3-[[[3-trifluromethyl-phenyl]methyl]amino]-pyrrolo[1, 2-a]pyrazine-6-carboxamide;
(6S,8R)-N-[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-butenyl]-1-chloro-4,6,7,8-tetrahydro-4-oxo-8-(3-(2-naphthyl)propyl)-3-[[[3-trifluromethylphenyl]methyl]amino]-pyrrolo[1,2-a]pyrazine-6-carboxamide;
(6S,8R)-N-[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-ethyl]-1-chloro-4,6,7,8-tetrahydro-4-oxo-8-(3-(2-naphthyl)propyl)-3-[[[3-trifluromethylphenyl]methyl]amino]-pyrrolo[1,2-a]pyrazine-6-carboxamide;
(6S,8R)-N-[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-butenyl]-1-chloro-4,6,7,8-tetrahydro-4-oxo-8-(3-(2-naphthyl)propyl)-3-[[[3-trifluromethylthiophenyl]methyl]amino]-pyrrolo[1,2-a]pyrazine-6-carboxamide;
(6S,8R)-N-[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-ethyl]-1-chloro-4,6,7,8-tetrahydro-4-oxo-8-(3-(2-naphthyl)propyl)-3-[[[3-trifluromethylthiophenyl]methyl]amino]-pyrrolo[1,2-a]pyrazine-6-carboxamide;
(6S,8R)-N-[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-[2,2-difluoroethyl]]-1-chloro-4,6,7,8-tetrahydro-4-oxo-8-(3-(2-naphthyl)propyl)-3-[[[3-trifluoromethylphenyl]methyl]amino]-pyrrolo[1,2-a]pyrazine-6-carboxamide;
(6S,8R)-N-[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-[2,2-difluoroethyl]]-1-chloro-4,6,7,8-tetrahydro-4-oxo-8-(3-(2-naphthyl)propyl)-3-[[[3-trifluoromethylthiophenyl]methyl]amino]-pyrrolo[1,2-a]pyrazine-6-carboxamide;
(6S,8R)-N-[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-butenyl]-1-chloro-4,6,7,8-tetrahydro-4-oxo-8-(3-phenylpropyl)-3-[2-propyl]amino]-pyrolo[1,2-a]pyrazine-6-carboxamide;
(6S,8R)-N-[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-butenyl]-1-chloro-4,6,7,8-tetrahydro-4-oxo-8-(3-phenylpropyl)-3-(2-methylpropyl)amino]-pyrrolo[1,2-a]pyrazine-6-carboxamide;
(6S,8R)-N-[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-butenyl]-1-chloro-4,6,7,8-tetrahydro-4-oxo-8-(3-phenylpropyl)-3-(cyclohexylmethyl)amino]-pyrrolo[1,2-]pyrazine-6-carboxamide;
(6S,8R)-N-[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-butenyl]-1-chloro-4,6,7,8-tetrahydro-4-oxo-8-(3-phenylpropyl)-3-[[[3-trifluoromethoxyphenyl]methyl]amino]-pyrrolo[1,2-a]pyrazine-6-carboxamide;
(6S,8R)-N-[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-butenyl]-1-chloro-4,6,7,8-tetrahydro-4-oxo-8-(3-phenylpropyl)-3-[[[2-difluoromethoxyphenyl]methyl]amino]-pyrrolo[1,2-a]pyrazine-6-carboxamide;
(6S,8R)-N-[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-butenyl]-1-chloro-4,6,7,8-tetrahydro-4-oxo-8-(3-phenylpropyl)-3-[[[2-pyridinyl]methyl]amino]-pyrrolo[1,2-a]pyrazine-6-carboxamide;
(6S,8R)-N-[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-butenyl]-1-chloro-4,6,7,8-tetrahydro-4-oxo-8-(3-phenylpropyl)-3-[[[4-pyridinyl]methyl]amino]-pyrrolo[1,2-a]pyrazine-6-carboxamide;
(6S,8R)-N-[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-butenyl]-1-chloro-4,6,7,8-tetrahydro-4-oxo-8-(3-phenylpropyl)-3-[[[3-pyridinyl]methyl]amino]-pyrrolo[1,2-a]pyrazine-6-carboxamide;
(6S,8R)-N-[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-butenyl]-1-chloro-4,6,7,8-tetrahydro-4-oxo-3-[[[3-trifluoromethylphenyl]methyl]amino]-pyrrolo[1,2-a]pyrazine-6-carboxamide;
(6S,8R)-N-[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-butenyl]-1-chloro-4,6,7,8-tetrahydro-4-oxo-3-[[[5-methyl-2-pyrazinyl)methyl]amino]-pyrrolo[1,2-a]pyrazine-6-carboxamide;
(6S,8R)-N-[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-butenyl]-4,6,7,8-tetrahydro-4-oxo-3-[[[3-trifluoromethylphenyl]methyl]amino]-pyrrolo[1,2-a]pyrazine-6-carboxamide;
(6S,8R)-N-[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-butenyl]-1-chloro-4,6,7,8-tetrahydro-4-oxo-3-[[[tert-butoxylcarbonyl]methyl]amino]-pyrrolo[1,2-a]pyrazine-6-carboxamide;
(6S,8R)-N-[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-butenyl]-1-chloro-4,6,7,8-tetrahydro-4-oxo-3-[[(2-tert-butoxylcarbonyl)ethyl]amino]-pyrrolo[1,2-a]pyrazine-6-carboxamide;
[(1R-1-[[[(6S,8R)-1-chloro-4,6,7,8-tetrahydro-4-oxo-8-(3-phenylpropyl)-3-[[[3-(trifluoromethyl)phenyl]methyl]-amino]pyrrolo[1,2-a]pyrazin-6-yl]carbonyl]amino]-3-butenyl]-boronic acid;
[(1R-1-[[[(6S,8R)-1-chloro-4,6,7,8-tetrahydro-4-oxo-8-[3-(2-naphthyl)propyl]-3-[[[3-(trifluoromethyl)phenyl]methyl]-amino]pyrrolo[1,2-a]pyrazin-6-yl]carbonyl]amino]-3-butenyl]-boronic acid; and
[(1R-1-[[[(6S,8R)-1-chloro-4,6,7,8-tetrahydro-4-oxo-8-[3-(2-naphthyl)propyl]-3-[[[3-(trifluoromethyl)phenyl]methyl]-amino]pyrrolo[1,2-a]pyrazin-6-yl]carbonyl]amino]-3-ethyl]-boronic acid.
In a particularly preferred embodiment, the present invention provides compounds of Formula (II-r) 
or pharmaceutically acceptable salt form thereof.
In a more particularly preferred embodiment, the present invention provides compounds of Formula (IIa-r): 
or pharmaceutically acceptable salt form thereof.
In another embodiment, the present invention provides a novel pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of Formula (I), (Ia), (Ib), (Ic), (II), (IIa) or pharmaceutically acceptable salt form thereof.
In another embodiment, the present invention provides a novel method of treating HCV infection which comprises administering to a host in need of such treatment a therapeutically effective amount of a compound of Formula Formula (I), (Ia), (Ib), (Ic), (II), (IIa) or pharmaceutically acceptable salt form thereof.
In another embodiment, the present invention provides novel compounds of Formula (I), (Ia), (Ib), (Ic), (II), (IIa) or pharmaceutically acceptable salt forms thereof for use in therapy.
In another embodiment, the present invention provides the use of novel compounds of Formula (I), (Ia), (Ib), (Ic), (II), (IIa) or pharmaceutically acceptable salt forms thereof for the manufacture of a medicament for the treatment of HCV.
The compounds herein described have asymmetric centers. Compounds of the present invention containing an asymmetrically substituted atom may be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms or by synthesis from optically active starting materials. Geometric isomers of double bonds such as olefins and Cxe2x95x90N double bonds can also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. Cis and trans geometric isomers of the compounds of the present invention are described and may be isolated as a mixture of isomers or as separated isomeric forms. All chiral, diastereomeric, racemic forms and all geometric isomeric forms of a structure are intended, unless the specific stereochemistry or isomeric form is specifically indicated. All processes used to prepare compounds of the present invention and intermediates made therein are considered to be part of the present invention.
The term xe2x80x9csubstituted,xe2x80x9d as used herein, means that any one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom""s normal valency is not exceeded, and that the substitution results in a stable compound. When a substituent is keto (i.e., xe2x95x90O), then 2 hydrogens on the atom are replaced. Keto substituents are not present on aromatic moieties. When a ring system (e.g., carbocyclic or heterocyclic) is said to be substituted with a carbonyl group or a double bond, it is intended that the carbonyl group or double bond be part (i.e., within) of the ring.
The present invention is intended to include all isotopes of atoms occurring in the present compounds. Isotopes include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include tritium and deuterium. Isotopes of carbon include C-13 and C-14.
When any variable (e.g., R1a) occurs more than one time in any constituent or formula for a compound, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be substituted with 0-3 R1a, then said group may optionally be substituted with up to three R1a groups and R1a at each occurrence is selected independently from the definition of R1a. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
When a bond to a substituent is shown to cross a bond connecting two atoms in a ring, then such substituent may be bonded to any atom on the ring. When a substituent is listed without indicating the atom via which such substituent is bonded to the rest of the compound of a given formula, then such substituent may be bonded via any atom in such substituent. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
As used herein, xe2x80x9calkylxe2x80x9d or xe2x80x9calkylenexe2x80x9d is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. For example, xe2x80x9cC1-C10 alkylxe2x80x9d (or alkylene), is intended to include C1, C2, C3, C4, C5, C6, C7, C8, C9, and C10 alkyl groups. Additionally, for example, xe2x80x9cC1-C6 alkylxe2x80x9d denotes alkyl having 1 to 6 carbon atoms. Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, n-pentyl, n-hexyl, 2-methylbutyl, 2-methylpentyl, 2-ethylbutyl, 3-methylpentyl, and 4-methylpentyl.
xe2x80x9cAlkenylxe2x80x9d or xe2x80x9calkenylenexe2x80x9d is intended to include hydrocarbon chains of either a straight or branched configuration having the specified number of carbon atoms and one or more unsaturated carbon-carbon bonds which may occur in any stable point along the chain. For example, xe2x80x9cC2-C6 alkenylxe2x80x9d (or alkenylene), is intended to include C2, C3, C4, C5, and C6 alkenyl groups. Examples of alkenyl include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3, pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-methyl-2-propenyl, 4-methyl-3-pentenyl, and the like.
xe2x80x9cAlkynylxe2x80x9d or xe2x80x9calkynylenexe2x80x9d is intended to include hydrocarbon chains of either a straight or branched configuration and one or more carbon-carbon triple bonds which may occur in any stable point along the chain. For example, xe2x80x9cC2-C6 alkynylxe2x80x9d (or alkynylene), is intended to include C2, C3, C4, C5, and C6 alkynyl groups; such as ethynyl, propynyl, butynyl, pentynyl, hexynyl and the like.
xe2x80x9cCycloalkylxe2x80x9d is intended to include saturated ring groups, having the specified number of carbon atoms. For example, xe2x80x9cC3-C6 cycloalkylxe2x80x9d denotes such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
xe2x80x9cAlkoxyxe2x80x9d or xe2x80x9calkyloxyxe2x80x9d represents an alkyl group as defined above with the indicated number of carbon atoms attached through an oxygen bridge. For example, xe2x80x9cC1-C6 alkoxyxe2x80x9d (or alkyloxy), is intended to include C1, C2, C3, C4, C5, and C6 alkoxy groups. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy, n-pentoxy, and s-pentoxy. Similarly, xe2x80x9calkylthioxe2x80x9d or xe2x80x9cthioalkoxyxe2x80x9d represents an alkyl group as defined above with the indicated number of carbon atoms attached through a sulphur bridge; for example methyl-Sxe2x80x94, ethyl-Sxe2x80x94, and the like.
xe2x80x9cHaloxe2x80x9d or xe2x80x9chalogenxe2x80x9d as used herein refers to fluoro, chloro, bromo, and iodo; and xe2x80x9ccounterionxe2x80x9d is used to represent a small, negatively charged species such as chloride, bromide, hydroxide, acetate, sulfate, and the like.
xe2x80x9cHaloalkylxe2x80x9d is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, substituted with 1 or more halogen (for example xe2x80x94CvFw where v=1 to 3 and w=1 to (2 v+1)). Examples of haloalkyl include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl, 2,2,2-trifluoroethyl, heptafluoropropyl, and heptachloropropyl. Examples of haloalkyl also include xe2x80x9cfluoroalkylxe2x80x9d which is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, substituted with 1 or more fluorine atoms.
xe2x80x9cHaloalkoxyxe2x80x9d or xe2x80x9chaloalkyloxyxe2x80x9d represents a haloalkyl group as defined above with the indicated number of carbon atoms attached through an oxygen bridge. For example, xe2x80x9cC1-C6 haloalkoxyxe2x80x9d, is intended to include C1, C2, C3, C4, C5, and C6 haloalkoxy groups. Examples of haloalkoxy include, but are not limited to, trifluoromethoxy, 2,2,2-trifluoroethoxy, pentafluorothoxy, and the like. Similarly, xe2x80x9chaloalkylthioxe2x80x9d or xe2x80x9cthiohaloalkoxyxe2x80x9d represents a haloalkyl group as defined above with the indicated number of carbon atoms attached through a sulphur bridge; for example trifluoromethyl-Sxe2x80x94, pentafluoroethyl-Sxe2x80x94, and the like.
As used herein, xe2x80x9ccarbocyclexe2x80x9d is intended to mean any stable 3, 4, 5, 6, or 7-membered monocyclic or bicyclic or 7, 8, 9, 10, 11, 12, or 13-membered bicyclic or tricyclic, any of which may be saturated, partially unsaturated, or aromatic. Examples of such carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, cyclooctyl, [3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane (decalin), [2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, adamantyl, or tetrahydronaphthyl (tetralin). Preferred carbocycles, unless otherwise specified, are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and phenyl.
As used herein, the term xe2x80x9cheterocyclexe2x80x9d or xe2x80x9cheterocyclic groupxe2x80x9d is intended to mean a stable 5, 6, or 7-membered monocyclic or bicyclic or 7, 8, 9, 10, 11, 12, 13, or 14-membered bicyclic heterocyclic ring which is saturated partially unsaturated or unsaturated (ie. aromatic or xe2x80x9cheteroarylxe2x80x9d), and which consists of carbon atoms and 1, 2, 3 or 4 heteroatoms independently selected from the group consisting of N, O and S; and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring. The nitrogen and sulfur heteroatoms may optionally be oxidized to xe2x80x94NOxe2x80x94, xe2x80x94SOxe2x80x94, or xe2x80x94SO2xe2x80x94. The heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom which results in a stable structure. The heterocyclic rings described herein may be substituted on carbon or on a nitrogen atom if the resulting compound is stable. If specifically noted, a nitrogen in the heterocycle may optionally be quaternized. It is preferred that when the total number of S and O atoms in the heterocycle exceeds 1, then these heteroatoms are not adjacent to one another. It is preferred that the total number of S and O atoms in the heterocycle is not more than 1.
Examples of heterocycles include, but are not limited to, 2-pyrrolidonyl, 2H,6H-1,5,2-dithiazinyl, 2H-pyrrolyl, 3H-indolyl, 4-piperidonyl, 4aH-carbazole, 4H-quinolizinyl, 6H-1,2,5-thiadiazinyl, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzoxazolinyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazalonyl, carbazolyl, 4aH-carbazolyl, b-carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, imidazolopyridinyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, isatinoyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isothiazolopyridinyl, isoxazolyl, isoxazolopyridinyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolopyridinyl, oxazolidinylperimidinyl, oxindolyl, phenanthridinyl, phenanthrolinyl, phenarsazinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, pteridinyl, piperidonyl, 4-piperidonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolopyridinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, carbolinyl, tetrazolyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thiazolopyridinyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, and xanthenyl.
Preferred 5 to 10 membered heterocycles include, but are not limited to, pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, pyrazinyl, piperazinyl, piperidinyl, imidazolyl, imidazolidinyl, indolyl, tetrazolyl, isoxazolyl, morpholinyl, oxazolyl, oxazolidinyl, tetrahydrofuranyl, thiadiazinyl, thiadiazolyl, thiazolyl, triazinyl, triazolyl, benzimidazolyl, 1H-indazolyl, benzofuranyl, benzothiofuranyl, benztetrazolyl, benzotriazolyl, benzisoxazolyl, benzoxazolyl, oxindolyl, benzoxazolinyl, benzthiazolyl, benzisothiazolyl, isatinoyl, isoquinolinyl, octahydroisoquinolinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, isoxazolopyridinyl, quinazolinyl, quinolinyl, isothiazolopyridinyl, thiazolopyridinyl, oxazolopyridinyl, imidazolopyridinyl, and pyrazolopyridinyl.
Preferred 5 to 6 membered heterocycles include, but are not limited to, pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, pyrazinyl, piperazinyl, piperidinyl, imidazolyl, imidazolidinyl, indolyl, tetrazolyl, isoxazolyl, morpholinyl, oxazolyl, oxazolidinyl, tetrahydrofuranyl, thiadiazinyl, thiadiazolyl, thiazolyl, triazinyl, and triazolyl. Also included are fused ring and spiro compounds containing, for example, the above heterocycles.
As used herein, the term xe2x80x9carylxe2x80x9d, xe2x80x9cC6-C10 arylxe2x80x9d or xe2x80x9caromatic residuexe2x80x9d, is intended to mean an aromatic moiety containing, if specified, the specified number of carbon atoms; for example phenyl, pyridinyl or naphthyl. Unless otherwise specified, xe2x80x9carylxe2x80x9d, xe2x80x9cC6-C10 arylxe2x80x9d or xe2x80x9caromatic residuexe2x80x9d may be unsubstituted or substituted with 0 to 3 groups selected from H, OH, OCH3, Cl, F, Br, I, CN, NO2, NH2, N(CH3)H, N(CH3)2, CF3, OCF3, C(xe2x95x90O)CH3, SCH3, S(xe2x95x90O)CH3, S(xe2x95x90O)2CH3, CH3, CH2CH3, CO2H, and CO2CH3.
The term xe2x80x9camino acidxe2x80x9d as used herein means an organic compound containing both a basic amino group and an acidic carboxyl group. Included within this term are natural amino acids (e.g., L-amino acids), modified and unusual amino acids (e.g., D-amino acids), as well as amino acids which are known to occur biologically in free or combined form but usually do not occur in proteins. Included within this term are modified and unusual amino acids, such as those disclosed in, for example, Roberts and Vellaccio (1983) The Peptides, 5: 342-429, the teaching of which is hereby incorporated by reference. xe2x80x9cNatural amino acidsxe2x80x9d include, but are not limited to, alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, serine, threonine, tyrosine, tyrosine, tryptophan, proline, and valine. Natural non-protein amino acids include, but are not limited to arginosuccinic acid, citrulline, cysteine sulfinic acid, 3,4-dihydroxyphenylalanine, homocysteine, homoserine, ornithine, 3-monoiodotyrosine, 3,5-diiodotryosine, 3,5,5xe2x80x2-triiodothyronine, and 3,3xe2x80x2,5,5xe2x80x2-tetraiodothyronine. Modified or unusual amino acids which can be used to practice the invention include, but are not limited to, D-amino acids, hydroxylysine, 4-hydroxyproline, an N-CBZ-protected amino acid, 2,4-diaminobutyric acid, homoarginine, norleucine, N-methylaminobutyric acid, naphthylalanine, phenylglycine, xcex2-phenylproline, tert-leucine, 4-aminocyclohexylalanine, N-methyl-norleucine, 3,4-dehydroproline, N,N-dimethylaminoglycine, N-methylaminoglycine, 4-aminopiperidine-4-carboxylic acid, 6-aminocaproic acid, trans-4-(aminomethyl)-cyclohexanecarboxylic acid, 2-, 3-, and 4-(aminomethyl)-benzoic acid, 1-aminocyclopentanecarboxylic acid, 1-aminocyclopropanecarboxylic acid, and 2-benzyl-5-aminopentanoic acid.
As used throughout the specification, the following abbreviations for amino acid residues or amino acids apply:
Abu is L-aminobutyric acid;
Ala is L-alanine;
Alg is L-2-amino-4-pentenoic acid;
Ape is L-2-aminopentanoic acid;
Arg is L-arginine;
Asn is L-asparagine;
Asp is L-aspartic acid;
Aze is azedine-2-carboxlic acid;
Cha is L-2-amino-3-cyclohexylpropionic acid;
Cpa is L-2-amino-3-cyclopropylpropionic acid
Cpg is L-2-amino-2-cyclopropylacetic acid;
Cys is L-cysteine;
Dfb is L-4,4xe2x80x2-difluoro-1-amino-butyric acid;
Dpa is L-2-amino-3,3-diphenylpropionic acid
Gln is L-glutamine;
Glu is L-glutamic acid;
Gly is glycine;
His is L-histidine;
HomoLys is L-homolysine;
Hyp is L-4-hydroxyproline;
Ile is L-isoleucine;
Irg is isothiouronium analog of L-Arg;
Leu is L-leucine;
Lys is L-lysine;
Met is L-methionine;
Orn is L-ornithine;
Phe is L-phenylalanine;
Phe(4-fluoro) is para-fluorophenylalanine;
Pro is L-proline;
Sar is L-sarcosine;
Ser is L-serine;
Thr is L-threonine;
Tpa is L-2-amino-5,5,5-trifluoropentanoic acid;
Trp is L-tryptophan;
Tyr is L-tyrosine; and
Val is L-valine.
xe2x80x9cAmino acid residuexe2x80x9d as used herein, refers to natural, modified or unnatural amino acids of either D- or L-configuration and means an organic compound containing both a basic amino group and an acidic carboxyl group. Natural amino acids residues are Ala, Arg, Asn, Asp, Aze, Cys, Gln, Glu, Gly, His, Hyp, Ile, Irg Leu, Lys, Met, Orn, Phe, Phe(4-fluoro), Pro, Sar, Ser, Thr, Trp, Tyr, and Val. Roberts and Vellaccio, The Peptides, Vol 5; 341-449 (1983), Academic Press, New York, discloses numerous suitable unnatural amino acids and is incorporated herein by reference for that purpose. Additionally, said reference describes, but does not extensively list, acylic N-alkyl and acyclic xcex1,xcex1-disubstituted amino acids. Included in the scope of the present invention are N-alkyl, aryl, and alkylaryl analogs of amino acid residues. Similarly, alkyl, aryl, and alkylaryl maybe substituted for the alpha hydrogen. Illustrated below are examples of N-alkyl and alpha alkyl amino acid residues, respectively. 
Unnatural amino acids that fall within the scope of xe2x80x9camino acid residuexe2x80x9d are by way of example and without limitation: 2-aminobutanoicacid, 2-aminopentanoic acid, 2-aminohexanoic acid, 2-aminoheptanoicacid, 2-aminooctanoic acid, 2-aminononanoic acid, 2-aminodecanoic acid, 2-aminoundecanoic acid, 2-amino-3,3-dimethylbutanoic acid, 2-amino-4,4-dimethylpentanoic acid, 2-amino-3-methylhexanoic acid, 2-amino-3-methylheptanoic acid, 2-amino-3-methyloctanoic acid, 2-amino-3-methylnonanoic acid, 2-amino-4-methylhexanoic acid, 2-amino-3-ethylpentanoic acid, 2-amino-3,4-dimethylpentanoic acid, 2-amino-3,5-dimethylhexanoic acid, 2-amino-3,3-dimethylpentanoic acid, 2-amino-3-ethyl-3-methylpentanoic acid, 2-amino-3,3-diethylpentanoic acid, 2-amino-5-methylhexanoic acid, 2-amino-6-methylheptanoic, 2-amino-7-methyloctanoic, 2-amino-2-cyclopentylacetic, 2-amino-2-cylcohexylacetic acid, 2-amino-2-(1-methylcylcohexyl)acetic acid, 2-amino-2-(2-methyl-1-methylcylcohexyl)acetic acid, 2-amino-2-(3-methyl-1-methylcylcohexyl)acetic acid, 2-amino-2-(4-methyl-1-methylcylcohexyl)acetic acid, 2-amino-2-(1-ethylcycolhexyl)acetic acid, 2-amino-3-(cyclohexyl)propanoic acid, 2-amino-4-(cyclohexyl)butanoic acid, 2-amino-3-(1-adamantyl)propanoic acid, 2-amino-3-butenoic acid, 2-amino-3-methyl-3-butenoic acid, 2-amino-4-pentenoic acid, 2-amino-4-hexenoic acid, 2-amino-5-heptenoic acid, 2-amino-4-methyl-4-hexenoic acid, 2-amino-5-methyl-4-hexenoic acid, 2-amino-4-methy-5-hexenoic acid, 2-amino-6-heptenoic acid, 2-amino-3,3,4-trimethyl-4-pentenoic acid, 2-amino-4-chloro-4-pentenoic, 2-amino-4,4-dichloro-3-butenoic acid, 2-amino-3-(2-methylenecyclopropyl)-propanoic acid, 2-amino-2-(2-cyclopentenyl)acetic acid, 2-amino-2-(cyclohexenyl)acetic acid, 2-amino-3-(2-cyclopentenyl)propanoic acid, 2-amino-3-(3-cyclopentenyl)propanoic acid, 2-amino-3-(1-cyclohexyl)propanoic acid, 2-amino-2-(1-cyclopentenyl)acetic acid, 2-amino-2-(1-cylcohexyl)acetic acid, 2-amino-2-(1-cylcoheptenyl)acetic acid, 2-amino-2-(1-cyclooctenyl)acetic acid, 2-amino-3-(1-cycloheptenyl)propanoic acid, 2-amino-3-(1,4-cyclohexadienyl)propanoic acid, 2-amino-3-(2,5-cyclohexadienyl)propanoic acid, 2-amino-2-(7-cycloheptatrienyl)acetic acid, 2-amino-4,5-hexadienoic acid, 2-amino-3-butynoic acid, 2-amino-4-pentyoic acid, 2-amino-4-hexynoic acid, 2-amino-4-hepten-6-ynoic acid, 2-amino-3-fluoropropanoic acid, 2-amino-3,3,3-trifluoropropanoic acid, 2-amino-3-fluorobutanoic acid, 2-amino-3-fluoropentanoic acid, 2-amino-3-fluorohexanoic acid, 2-amino-3,3-difluorobutanoic acid, 2-amino-3,3-difluoro-3-phenylpropanoic acid, 2-amino-3-perfluoroethylpropanoic acid, 2-amino-3-perfluoropropylpropanoic acid, 2-amino-3-fluoro-3-methylbutanoic acid, 2-amino-5,5,5-trifluoropentanoic acid, 2-amino-3-methyl-4,4,4-trifluorobutanoic acid, 2-amino-3-trifluoromethyl-4,4,4-trifluorobutanoic acid, 2-amino-3,3,4,4,5,5-heptafluoropentanoic acid, 2-amino-3-methyl-5-fluoropentanoic acid, 2-amino-3-methyl-4-fluoropentanoic acid, 2-amino-5,5-difluorohexanoic acid, 2-amino-4-(fluoromethyl)-5-fluoropentanoic acid, 2-amino-4-trifluoromethyl-5,5,5-trifluoropentanoic acid, 2-amino-3-fluoro-3-methylbutanoic acid, 2-amino-3-fluoro-3-phenylpentanoic acid, 2-amino-2-(1-fluorocyclopentyl)acetic acid, 2-amino-2-(1-fluorocyclohexyl)acetic acid, 2-amino-3-chloropropanoic acid acid, 2-amino-3-chlorobutanoic acid acid, 2-amino-4,4-dichlorobutanoic acid acid, 2-amino4,4,4-trichlorobutanoic acid, 2-amino-3,4,4-trichlorobutanoic acid, 2-amino-6-chlorohexanoic acid, 2-amino-4-bromobutanoic acid, 2-amino-3-bromobutanoic acid, 2-amino-3-mercaptobutanoic acid, 2-amino-4-mercaptobutanoic acid, 2-amino-3-mercapto-3,3-dimethylpropanoic acid, 2-amino-3-mercapto-3-methylpentanoic acid, 2-amino-3-mercaptopentanoic acid, 2-amino-3-mercapto-4-methylpentanoic acid, 2-amino-3-methyl-4-mercaptopentanoic acid, 2-amino-5-mercapto-5-methylhexanoic acid, 2-amino-2-(1-mercaptocyclobutyl)acetic acid, 2-amino-2-(1-mercaptocyclopentyl)acetic acid, 2-amino-2-(1-mercaptocyclohexyl)acetic acid, 2-amino-5-(methylthio)pentanoic acid, 2-amino-6-(methylthio)hexanoic acid, 2-amino-4-methylthio-3-phenylbutanoic acid, 2-amino-5-ethylthio-5-methylpentanoic acid, 2-amino-5-ethylthio-3,5,5-trimethylpentanoic acid, 2-amino-5-ethylthio-5-phenylpentanoic acid, 2-amino-5-ethylthio-5-pentanoic acid, 2-amino-5-butylthio-5-methylpentanoic acid, 2-amino-5-butylthio-3,5,5-trimethylpentanoic acid, 2-amino-5-butylthio-5-phenylpentanoic acid, 2-amino-5-(butylthio)pentanoic acid, 2-amino-3-methy4-hydroselenopentanoic acid, 2-amino-4-methylselenobutanoic acid, 2-amino-4-ethylselenobutanoic acid, 2-amino-4-benzylselenobutanoic acid, 2-amino-3-methyl-4-(methylseleno)butanoic acid, 2-amino-3-(aminomethylseleno)propanoic acid, 2-amino-3-(3-aminopropylseleno)propanoic acid, 2-amino-4-methyltellurobutanoic acid, 2-amino-4-hydroxybutanoic acid, 2-amino-4-hydroxyhexanoic acid, 2-amino-3-hydroxypentanoic acid, 2-amino-3-hydroxyhexanoic acid, 2-amino-3methyl-4-hydroxybutanoic acid, 2-amino-3-hydroxy-3-methylbutanoic acid, 2-amino-6-hydroxyhexanoic acid, 2-amino-4-hydroxyhexanoic acid, 2-amino-3-hydroxy-4-methylpentanoic acid, 2-amino-3-hydroxy-3-methylpentanoic acid, 2-amino4-hydroxy-3,3-dimethylbutanoic acid, 2-amino-3-hydroxy4-methylpentanoic acid, 2-amino-3-hydroybutanedioic acid, 2-amino-3-hydroxy-3-phenyl-propanoic acid, 2-amino-3-hydroxy-3-(4-nitrophenyl)propanoic acid, 2-amino-3-hydroxy-3-(3-pyridyl)propanoic acid, 2-amino-2-(1-hydroxycyclopropyl)acetic acid, 2-amino-3-(1-hydroxycyclohexyl)propanoic acid, 2-amino-3-hydroxy-3-phenylpropanoic acid, 2-amino-3-hydroxy-3-[3-bis(2-chloroethyl)aminophenyl]propanoic acid, 2-amino-3-hydroxy-3-(3,4-dihydroxyphenyl)propanoic acid, 2-amino-3-hydroxy-3-(3,4-methylenedioxyphenyl)propanoic acid, 2-amino-4-fluoro-3-hydroxybutanoic acid, 2-amino-4,4,4-trichloro-3-hydroxybutanoic acid, 2-amino-3-hydroxy-4-hexynoic acid, 2-amino-3,4-dihydroxybutanoic acid, 2-amino-3,4,5,6-tetrahydroxyhexanoic acid, 2-amino-4,5-dihydroxy-3-methylpentanoic acid, 2-amino-5,6-dihydroxyhexanoic acid, 2-amino-5-hydroxy-4-(hydroxyrnethyl)pentanoic acid, 2-amino-4,5-dihydroxy-4-(hydroxymethyl)pentanoic acid, 2-amino-3-hydroxy-5-benzyloxypentanoic acid, 2-amino-3-(2-aminoethoxy)propanoic acid, 2-amino-4-(2-aminoethoxy)butanoic acid, 2-amino-4-oxobutanoic acid, 2-amino-3-oxobutanoic acid, 2-amino-4-methyl-3-oxopentanoic acid, 2-amino-3-phenyl-3-oxopropanoic acid, 2-amino-4-phenyl-3-oxobutanoic acid, 2-amino-3-methyl-4-oxopentanoic acid, 2-amino-4-oxo-4-(4-hydroxyphenyl)butanoic acid, 2-amino-4-oxo-4-(2-furyl)butanoic acid, 2-amino-4-oxo-4-(2-nitrophenyl)butanoic acid, 2-amino-4-oxo-4-(2-amino-4-chlorophenyl)butanoic acid, 2-amino-3-(4-oxo-1-cyclohexenyl)propanoic acid, 2-amino-3-(4-oxocyclohexanyl)propanoic acid, 2-amino-3-(2,5-dimethyl-3,6-dioxo-1,4-cydohexadienyl)propanoic acid, 2-amino-3-(1-hydroxy-5-methyl-7-oxo-cyclohepta-1,3,5-trien-2-yl)propanoic acid, 2-amino-3-(1-hydroxy-7-oxo-cyclohepta-1,3,5-trien-3-yl)propanoic acid, 2-amino-3-(1-hydroxy-7-oxo-cyclohepta-1,3,5-trien-4-yl)propanoic acid, 2-amino-4-methoxy-3-butenoic acid, 2-amino-4-(2-aminoethoxy)-3-butenoic acid, 2-amino-4-(2-amino-3-hydroxypropyl)-3-butenoic acid, 2-amino-2-(4-methoxy-1,4-cyclohexadienyl)acetic acid, 2-amino-3,3-diethoxypropanoic acid, 2-amino-4,4-dimethylbutanoic acid, 2-amino-2-(2,3-epoxycyclohexyl)acetic acid, 2-amino-3-(2,3-epoxycyclohexy)propanoic acid, 2-amino-8-oxo-9,10-epoxydecanoic acid, 2-amino-propanedioic acid, 2-amino-3-methylbutanedioic acid, 2-amino-3,3-dimethylbutanedioic acid, 2-amino4-methylpentanedioic acid, 2-amino-3-methylpentanedioic acid, 2-amino-3-phenylpentanedioic acid, 2-amino-3-hydroxypentanedioic acid, 2-amino-3-carboxypentanedioic acid, 2-amino-4-ethylpentanedioic acid, 2-amino-4-propylpentanedioic acid, 2-amino-4-isoamylpentanedioic acid, 2-amino-4-phenylpentanedioic acid, 2-amino-hexanedioic acid, 2-amino-heptanedioic acid, 2-amino-decanedioic acid, 2-amino-octanedioic acid, 2-amino-dodecanedioic acid, 2-amino-3-methylenebutanedioic acid, 2-amino-4-methylenepentanedioic acid, 2-amino-3-fluorobutanedioic acid, 2-amino-4-fluoropentanedioic acid, 2-amino-3,3-difluorobutanedioic acid, 2-amino-3-chloropentanedioic acid, 2-amino-3-hydroxybutanedioic acid, 2-amino-4-hydroxypentanedioic acid, 2-amino-4-hydroxyhexanedioic acid, 2-amino-3,4-dihydroxypentanedioic acid, 2-amino-3-(3-hydroxypropyl)butanedioic acid, 2-amino-3-(1-carboxy-4-hydroxy-2-cyclodienyl)propanoic acid, 2-amino-3-(aceto)butanedioic acid, 2-amino-3-cyanobutanedioic acid, 2-amino-3-(2-carboxy-6-oxo-6H-pyranyl)propanoic acid, 2-amino-3-carboxybutanedioic acid, 2-amino-4-carboxypentanedioic acid, 3-amido-2-amino-3-hydroxypropanoic acid, 3-amido-2-amino-3-methylpropanoic acid, 3-amido-2-amino-3-phenylpropanoic acid, 3-amido-2,3-diaminopropanoic acid, 3-amido-2-amino-3-[N-(4-hydroxyphenyl)amino]propanoic acid, 2,3-diaminopropanoic acid, 2,3-diaminobutanoic acid, 2,4-diaminobutanoic acid, 2,4-diamino-3-methylbutanoic acid, 2,4-diamino-3-phenylbutanoic acid, 2-amino-3-(methylamino)butanoic acid, 2,5-diamino-3-methylpentanoic acid, 2,7-diaminoheptanoic acid, 2,4-diaminoheptanoic acid, 2-amino-2-(2-piperidyl)acetic acid, 2-amino-2-(1-aminocyclohexyl)acetic acid, 2,3-diamino-3-phenylpropanoic acid, 2,3-diamino-3-(4-hydroxyphenyl)propanoic acid, 2,3-diamino-3-(4-methoxyphenyl)propanoic acid, 2,3-diamino-3-[4-(N,Nxe2x80x2-dimethyamino)phenyl]propanoic acid, 2,3-diamino-3-(3,4-dimethoxyphenyl)propanoic acid, 2,3-diamino-3-(3,4-methylenedioxyphenyl)propanoic acid, 2,3-diamino-3-(4-hydroxy-3-methoxyphenyl)propanoic acid, 2,3-diamino-3-(2-phenylethyl)propanoic acid, 2,3-diamino-3-propylpropanoic acid, 2,6-diamino-4-hexenoic acid, 2,5-diamino-4-fluoropentanoic acid, 2,6-diamino-5-fluorohexanoic acid, 2,6-diamino-4-hexynoic acid, 2,6-diamino-5,5-difluorohexanoic acid, 2,6-diamino-5,5-dimethylhexanoic acid, 2,5-diamino-3-hydroxypentanoic acid, 2,6-diamino-3-hydroxyhexanoic acid, 2,5-diamino-4-hydroxypentanoic acid, 2,6-diamino-4-hydroxyhexanoic acid, 2,6-diamino-4-oxohexanoic acid, 2,7-diaminooctanedioic acid, 2,6-diamino-3-carboxyhexanoic acid, 2,5-diamino-4-carboxypentanoic acid, 2-amino-4-(2-(N,Nxe2x80x2-diethylamino)ethyl)pentandioic acid, 2-amino-4-(N,Nxe2x80x2-diethylamino)pentandioic acid, 2-amino-4-(N-morpholino)pentandioic acid, 2-amino-4-(N,Nxe2x80x2-bis(2-chloroethyl)amino)pentandioic acid, 2-amino-4-(N,Nxe2x80x2-bis(2-hydroxyethyl)amino)pentandioic acid, 2,3,5-triaminopentanoic acid, 2-amino-3-(N-(2-aminethyl)amino)propanoic acid, 2-amino-3-((2-aminoethyl)seleno)propanoic acid, 2-amino-3-[(2-aminoethyl)thio]propanoic acid, 2-amino4-aminooxybutanoic acid, 2-amino-5-hydroxyaminopentanoic acid, 2-amino-5-[N-(5-nitro-2-pyrimidinyl)amino]pentanoic acid, 2-amino-4-[(7-nitro-2,1,3-benzoxadiazol-4-yl)amino]butanoic acid, 2-amino-3-guanidinopropanoic acid, 2-amino-3-guanidinobutanoic acid, 2-amino-4-guanidobutanoic acid, 2-amino-6-guanidohexanoic acid, 2-amino-6-ureidohexanoic acid, 2-amino-3-(2-iminoimidiazolin-4-yl)propanoic acid, 2-amino-2-(2-iminohexahydropyrimidin-4-yl)acetic acid, 2-amino-3-(2-iminohexahydropyrimidiny-4-yl)propanoic acid, 2-amino4-fluoro-5-guanidopentanoic acid, 2-amino-4-hydroxy-5-guanidopentanoic acid, 2-amino-4-guanidooxybutanoic acid, 2-amino-6-amidinohexanoic acid, 2-amino-5-(N-acetimidoylamino)pentanoic acid, 1-aminocyclopropanecarboxylic acid, 1-amino4-ethylcyclpropanecarboxylic acid, 1-aminocyclopentanecarboxylic acid, 1-aminocyclopentanecarboxylic acid, 1-amino-2,2,5,5-tetramethyl-cyclohexanecarboxylic acid, 1-aminocydoheptanecarboxylic acid, 1-aminocyclononanecarboxylic acid, 2-aminoindan-2-carboxylic acid, 2-aminonorbornane-2-carboxylic acid, 2-amino-3-phenylnorbornane-2-carboxylic acid, 3-aminotetrahydrothiophene-3-carboxylic acid, 1-amino-1,3-cyclohexanedicarboxylic acid, 3-aminopyrrolidine-3-carboxylic acid, 1,4-diaminocyclohexanecarboxylic acid, 6-alkoxy-3-amino-1,2,3,4-tetrahydrocarbazole-3-carboxylic acid, 2-aminobenzobicyclo[2,2,2]octane-2-carboxylic acid, 2-aminoindan-2-carboxylic acid, 1-amino-2-(3,4-dhydroxyphenyl)cyclopropanecarboxylic acid, 5,6-dialkoxy-2-aminoindane-2-carboxylic acid, 4,5-dihydroxy-2-aminoindan-2-caroxylic acid, 5,6-dihydroxy-2-aminotetralin-2-carboxylic acid, 2-amino-2-cyanoacetic acid, 2-amino-3-cyanopropanoic acid, 2-amino-4-cyanobutanoic acid, 2-amino-5-nitropentanoic acid, 2-amino-6-nitrohexanoic acid, 2-amino-4-aminooxybutanoic acid, 2-amino-3-(N-nitrosohydroxyamino)propanoic acid, 2-amino-3-ureidopropanoic acid, 2-amino-4-ureidobutanoic acid, 2-amino-3-phosphopropanoic acid, 2-amino-3-thiophosphopropanoic acid, 2-amino-4-methanephosphonylbutanoic acid, 2-amino-3-(trimethylsilyl)propanoic acid, 2-amino-3-(dimethyl(trimethylsilylmethylsilyl)propanoic acid, 2-amino-2-phenylacetic acid, 2-amino-2-(3-chlorophenyl)acetic acid, 2-amino-2-(4-chlorophenyl)acetic acid, 2-amino-2-(3-fluorophenyl)acetic acid, 2-amino-2-(3-methylphenyl)acetic acid, 2-amino-2-(4-fluorophenyl)acetic acid, 2-amino-2-(4-methylphenyl)acetic acid, 2-amino-2-(4-methoxyphenyl)acetic acid, 2-amino-2-(2-fluorophenyl)acetic acid, 2-amino-2-(2-methylphenyl)acetic acid, 2-amino-2-(4-chloromethylphenyl)acetic acid, 2-amino-2-(4-hydroxymethylphenyl)acetic acid, 2-amino-2-[4-(methylthiomethyl)phenyl]acetic acid, 2-amino-2-(4-bromomethylphenyl)acetic acid, 2-amino-2-(4-(methoxymethy)phenyl)acetic acid, 2-amino-2-(4-((N-benzylamino)methyl)phenyl)acetic acid, 2-amino-2-(4-hydroxylphenyl)acetic acid, 2-amino-2-(3-hydroxylphenyl)acetic acid, 2-amino-2-(3-carboxyphenyl)acetic acid, 2-amino-2-(4-aminophenyl)acetic acid, 2-amino-2-(4-azidophenyl)acetic acid, 2-amino-2-(3-t-butyl-4-hydroxyphenyl)acetic acid, 2-amino-2-(3,5-difluoro-4-hydroxyphenyl)acetic acid, 2-amino-2-(3,5-dihydroxyphenyl)acetic acid, 2-amino-2-(3-carboxy-4-hydroxyphenyl)acetic acid, 2-amino-2-(3,5-di-t-butyl-4-hydroxyphenyl)acetic acid, 2-amino-3-(2-methylphenyl)propanoic acid, 2-amino-3-(4-ethylphenyl)propanoic acid, 2-amino-3-(4-phenylphenyl)propanoic acid, 2-amino-3-(4-benzylphenyl)propanoic acid, 2-amino-3-(3-fluorophenyl)propanoic acid, 2-amino-3-(4-methylphenyl)propanoic acid, 2-amino-3-(4-fluorophenyl)propanoic acid, 2-amino-3-(4-chlorophenyl)propanoic acid, 2-amino-3-(2-chlorophenyl)propanoic acid, 2-amino-3-(4-bromophenyl)propanoic acid, 2-amino-3-(2-bromophenyl)propanoic acid, 2-amino-3-(3-hydroxyphenyl)propanoic acid, 2-amino-3-(2-hydroxyphenyl)propanoic acid, 2-amino-3-(4-mercaptophenyl)propanoic acid, 2-amino-3-(3-trifluoromethylphenyl)propanoic acid, 2-amino-3-(3-hydroxyphenyl)propanoic acid, 2-amino-3-(4-hydroxyphenyl)propanoic acid, 2-amino-3-(4-(hydroxymethy)phenyl]propanoic acid, 2-amino-3-[3-(hydroxyethyl)phenyl]propanoic acid, 2-amino-3-[3-(aminomethyl)phenyl]propanoic acid, 2-amino-3-(3-carboxyphenyl)propanoic acid, 2-amino-3-(4-nitrophenyl)propanoic acid, 2-amino-3-(4-aminophenyl)propanoic acid, 2-amino-3-(4-azidophenyl)propanoic acid, 2-amino-3-(4-cyanophenyl)propanoic acid, 2-amino-3-(4-acetophenyl)propanoic acid, 2-amino-3-(4-guanidinophenyl)propanoic acid, 2-amino-3-[4-(phenylazo)phenyl]propanoic acid, 2-amino-3-[4-(2-phenylethylenyl)phenyl]propanoic acid, 2-amino-3-(4-trialkylsilylphenyl)propanoic acid, 2-amino -3-(2,4-dimethylphenyl)propanoic acid, 2-amino-3-(2,3-dimethylphenyl)propanoic acid, 2-amino-3-(2,5-dimethylphenyl)propanoic acid, 2-amino-3-(3,5-dimethylphenyl)propanoic acid, 2-amino-3-(2,4,6-trimethylphenyl)propanoic acid, 2-amino-3-(3,4,5-trimethylphenyl)propanoic acid, 2-amino-3-(2,3,4,5,6-pentamethylphenyl)propanoic acid, 2-amino-3-(2,4,-difluorophenyl)propanoic acid, 2-amino-3-(3,4,-difluorophenyl)propanoic acid, 2-amino-3-(2,5,-difluorophenyl)propanoic acid, 2-amino-3-(2,6,-difluorophenyl)propanoic acid, 2-amino-3-(2,3,5,6-tetrafluorophenyl)propanoic acid, 2-amino-3-(3,5-dichloro-2,4,6-trifluorophenyl)propanoic acid, 2-amino-3-(2,3-difluorophenyl)propanoic acid, 2-amino-3-(2,3-bistrifluoromethylphenyl)propanoic acid, 2-amino-3-(2,4-bistrifluoromethylphenyl)propanoic acid, 2-amino-3-(2-chloro-5-trifluoromethylphenyl)propanoic acid, 2-amino-3-(2,5-difluorophenyl)propanoic acid, 2-amino-3-(2,3,4,5,6-pentafluorophenyl)propanoic acid, 2-amino-3-(2,3-dibromophenyl)propanoic acid, 2-amino-3-(2,5-dibromophenyl)propanoic acid, 2-amino-3-(3,4-dibromophenyl)propanoic acid, 2-amino-3-(3,4,5-triiodophenyl)propanoic acid, 2-amino-3-(2,3-dihydroxyphenyl)propanoic acid, 2-amino-3-(2,5-dihydroxyphenyl)propanoic acid, 2-amino-3-(2,6-dihydroxyphenyl)propanoic acid, 2-amino-3-(3-bromo-5-methoxyphenyl)propanoic acid, 2-amino-3-(2,5-dimethoxyphenyl)propanoic acid, 2-amino-3-(2,5-dimethoxy-4-methylphenyl)propanoic acid, 2-amino-3-(4-bromo-2,5-dimethoxyphenyl)propanoic acid, 2-amino-3-(3-carboxy-4-hydroxyphenyl)propanoic acid, 2-amino-3-(3-carboxy-4-aminophenyl)propanoic acid, 2-amino-3-(2-hydroxy-5-nitrophenyl)propanoic acid, 2-amino-3-(2-ethoxy-5-nitrophenyl)propanoic acid, 2-amino-3-(3,4,5-trimethoxyphenyl)propanoic acid, 2-amino-3-(4-azido-2-nitrophenyl)propanoic acid, 2-amino-3-(2-hydroxy-5-nitrophenyl)propanoic acid, 2-amino-3-(2,4-bis-trimethylsilylphenyl)propanoic acid, 2-amino-3-(4-hydroxy-3,5-di-t-butylphenyl)propanoic acid, 2-amino-3-(4-hydroxy-3-benzylphenyl)propanoic acid, 2-amino-3-(4-hydroxy-3-fluorophenyl)propanoic acid, 2-amino-3-(4-hydroxy-2,3,5,6-tetrafluorophenyl)propanoic acid, 2-amino-3-(4-hydroxy-3,5-dichlorophenyl)propanoic acid, 2-amino-3-(4-hydroxy-3-iodophenyl)propanoic acid, 2-amino-3-(4-hydroxy-3,5-diiodophenyl)propanoic acid, 2-amino-3-(4-hydroxy-2-hydroxyphenyl)propanoic acid, 2-amino-3-(4-hydroxy-3-hydroxymethylphenyl)propanoic acid, 2-amino-3-(4-hydroxy-2-hydroxy-6-methylphenyl)propanoic acid, 2-amino-3-(4-hydroxy-3-carboxyphenyl)propanoic acid, 2-amino-3-(4hydroxy-3,5-dinitrophenyl)propanoic acid, substituted thyronines, 2-amino-3-(3,4-dihydroxy-2-chlorophenyl)propanoic acid, 2-amino-3-(3,4-dihydroxy-2-bromophenyl)propanoic acid, 2-amino-3-(3,4-dihydroxy-2-fluorophenyl)propanoic acid, 2-amino-3-(3,4-dihydroxy-2-nitrophenyl)propanoic acid, 2-amino-3-(3,4-dihydroxy-2-methylphenyl)propanoic acid, 2-amino-3-(3,4-dihydroxy-2-ethylphenyl)propanoic acid, 2-amino-3-(3,4-dihydroxy-2-isopropylphenyl)propanoic acid, 2-amino-3-(2-t-butyl-4,5-dihydroxyphenyl)propanoic acid, 2-amino-3-(3-fluoro-4,5-dihydroxyphenyl)propanoic acid, 2-amino-3-(2-fluoro-4,5-dihydroxyphenyl)propanoic acid, 2-amino-3-(2,5,6-trifluoro-3,4-dihydroxyphenyl)propanolc acid, 2-amino-3-(2,6-dibromo-3,4-dihydroxyphenyl)propanoic acid, 2-amino-3-(5,6-dibromo-3,4-dihydroxyphenyl)propanoic acid, 2-amino-3-(2,4,5-trihydroxyphenyl)propanoic acid, 2-amino-3-(2,3,4-trihydroxyphenyl)propanoic acid, 2-amino-3-(3,4-dihydroxy-5-methoxyphenyl)propanoic acid, 2-amino-3-methyl-3-phenylpropanoic acid, 2-amino-3-ethyl-3-phenylpropanoic acid, 2-amino-3-isopropyl-3-phenylpropanoic acid, 2-amino-3-butyl-3-phenylpropanoic acid, 2-amino-3-benzyl-3-phenylpropanoic acid, 2-amino-3-phenylethyl-3-phenylpropanoic acid, 2-amino-3-(4-chlorophenyl)-3-phenylpropanoic acid, 2-amino-3-(4-methoxyphenyl)-3-phenylpropanoic acid, 2-amino-3,3-diphenylpropanoic acid, 2-amino-3-[4-(N,N- diethylamino)phenyl]heptanoic acid, 2-amino-3-[4-(N,N-diethylamino)phenyl]pentanoic acid, 2-amino-3-(3,4-dimethoxyphenyl)pentanoic acid, 2-amino-3-(3,4-dihydroxyphenyl)pentanoic acid, 2-amino-3-methyl-3-phenylbutanoic acid, 2-amino-3-ethyl-3-phenylpentanoic acid, 2-amino-3-methyl-3-phenylpentanoic acid, 2-amino-3,3-diphenylbutanoic acid, 2-amino-3-fluoro-3-phenylpropanoic acid, 2-amino-3-methylene-3-phenylpropanoic acid, 2-amino-3-methylmercapto-3-phenylpropanoic acid, 2-amino-4-methylmercapto-4-phenylbutanoic acid, 2-amino-4-(3,4-dihydroxyphenyl)butanoic acid, 2-amino-5-(4-methoxyphenyl)pentanoic acid, 2-amino-4-phenylbutanoic acid, 2-amino-5-phenylpentanoic acid, 2-amino-3,3-dimethyl-5-phenylpentanoic acid, 2-amino-4-phenyl-3-butenoic acid, 2-amino-4-phenoxybutanoic acid, 2-amino-5-phenoxypentanoic acid, 2-amino-2-(indanyl)acetic acid, 2-amino-2-(1-tetralyl)acetic acid, 2-amino-4,4-diphenylbutanoic acid, 2-amino-2-(2-naphthyl)acetic acid, 2-amino-3-(1-naphthyl)propanoic acid, 2-amino-3-(1-naphthyl)pentanoic acid, 2-amino-3-(2-naphthyl)propanoic acid, 2-amino-3-(1-chloro-2-naphthyl)propanoic acid, 2-amino-3-(1-bromo-2-naphthyDpropanoic acid, 2-amino-3-(4-hydroxy-1-naphthyl)propanoic acid, 2-amino-3-(4-methoxy-1-naphthyl)propanoic acid, 2-amino-3-(4-hydroxy-2-chloro-1-naphthyl)propanoic acid, 2-amino-3-(2-chloro-4-methoxy-1-naphthyl)propanoic acid, 2-amino-2-(2-anthryl)acetic acid, 2-amino-3-(9-anthryl)propanoic acid, 2-amino-3-(2-fluorenyl)propanoic acid, 2-amino-3-(4-fluorenyl)propanoic acid, 2-amino-3-(carboranyl)propanoic acid, 3-methylproline, 4-methylproline, 5-methylproline, 4,4-dimethylproline, 4-fluoroproline, 4,4-difluoroproline, 4-bromoproline, 4-chloroproline, 4-aminoproline, 3,4-dehydroproline, 4-methylproline, 4-methyleneproline, 4-mercaptoproline, 4-(4-methoxybenzylmercapto)proline, 4-hydroxymethylproline, 3-hydroxyproline, 3-hydroxy-5-methylproline, 3,4-dihydroxyproline, 3-phenoxyproline, 2-aminoproline, 5-aminoproline, 3-carbamylalkylproline, 4-cyano-5-methyl-5-carboxyproline, 4,5-dicarboxyl-5-methylproline, 2-aziridinecarboxylic acid, 2-azetidinecarboxylic acid, 4-methyl-2-azetidinecarboxylic acid, pipecolic acid, 1,2,3,6-tetrahydropicolinic acid, 3,4-methyleneproline, 2.4-methyleneproline, 4-aminopipecolic acid, 5-hydroxypipecolic acid, 4,5-dihydroxypipecolic acid, 5,6-dihydroxy-2,3-dihydroindole-2-carboxylic acid, 1,2,3,4-tetrahydroquinoline-2-carboxylic acid, 6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, 6-hydroxy-1-methyl-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, 6,7-dihydroxy-1-methyl-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, 1,3-oxazolidine-4-carboxylic acid, 1,2-oxazolidine-3-carboxylic acid, perhydro-1,4-thiazine-3-carboxylic acid, 2,2-dimethylthiazolidine-4-carboxylic acid, perhydro-1,3-thlazine-2-carboxylic acid, selenazolidine4-carboxylic acid, 2-phenylthiazolidine4-carboxylic acid, 2-(4-carboxylicyl)thiazolidine-4-carboxylic acid, 1,2,3,4,4a,9a-hexahydro-beta-carboline-3-carboxylic acid, 2,3,3a,8a-tetrahydropyrrolo(2,3b)indole-2-carboxylic acid, 2-amino-3-(2-pyridyl)propanoic acid, 2-amino-3-(3-pyridyl)propanoic acid, 2-amino-3-(4-pyridyl)propanoic acid, 2-amino-3-(2-bromo-3-pyridyl)propanoic acid, 2-amino-3-(2-bromo-4-pyridyl)propanoic acid, 2-amino-3-(2-bromo-5-pyridyl)propanoic acid, 2-amino-3-(2-bromo-6-pyridyl)propanoic acid, 2-amino-3-(2-chloro-3-pyridyl)propanoic acid, 2-amino-3-(2-chloro-4-pyridyl)propanoic acid, 2-amino-3-(2-chloro-5-pyridyl)propanoic acid, 2-amino-3-(2-chloro-6-pyridyl)propanoic acid, 2-amino-3-(2-fluoro-3-pyridyl)propanoic acid, 2-amino-3-(2-fluoro-4-pyridyl)loropanoic acid, 2-amino-3-(2-fluoro-5-pyridyl)propanoic acid, 2-amino-3-(2-fluoro-6-pyridyl)proloanoic acid, 2-amino-3-(1,2-dihydro-2-oxo-3-pyridyl)propanoic acid, 2-amino-3-(1,2-dihydro-2-oxo4-pyridyl)propanoic acid, 2-amino-3-(1,2-dihydro-2-oxo-5-pyridyl)propanoic acid, 2-amino-3-(1,2-dihydro-2-oxo-6-pyridyl)propanoic acid, 2-amino-3-(5-hydroxy-2-pyridyl)propanoic acid, 2-amino-3-(5-hydroxy-6-iodo-2-pyridyl)propanoic acid, 2-amino-3-(3-hydroxy-4-oxo-1,4dihydro-1-pyridyl)propanoic acid, N-(5-caroxyl-5-aminopentyl)pyridinium chloride, 1,2, 5-trimethyl-4-(2-amino-2-carboxy-1-hydroxyethyl)pyridinium chloride, 2-amino-2-(5-chloro-2-pyridyl)acetic acid, N-(3-amino -3-carboxypropyl)pyridinium chloride, 2-amino -3-(2-pyrryl)propanoic acid, 2-amino-3-(1-pyrryl)propanoic acid, 2-amino-4-(1-pyrryl)butanoic acid, 2-amino-5-(1-pyrryl)pentanoic acid, 2-amino-3-(5-imidazolyl) -3-methylpropanoic acid, 2-amino-3-(5-imidazolyl) -3-ethylpropanoic acid, 2-amino-3-hexyl-3-(5-imidazolyl)propanoic acid, 2-amino-3-hydroxy-3-(5-imidazolyl)propanoic acid, 2-amino-3-(4-nitro-5-imidazolyl)proloanoic acid, 2-amino-3-(4-methyl-5-imidazolyl)propanoic acid, 2-amino-3-(2-methyl-5-imidazolyl)propanoic acid, 2-amino-3-(4-fluoro-5-imidazolyl)propanoic acid, 2-amino-3-(2-fluoro-5-imidazolyl)propanoic acid, 2-amino-3-(2-amino-5-imidazolyl)propanoic acid, 2-amino-3-(2-phenylaza-5-imidazolyl)propanoic acid, 2-amino-3-(1-methyl-2-nitro-5-imidazolyl)propanoic acid, 2-amino-3-(1-methyl4-nitro-5-imidazolyl)propanoic acid, 2-amino-3-(1-methyl-5-nitro-5-imidazolyl)propanoic acid, 2-amino-3-(2-mercapto-5-imidazolyl)propanoic acid, 2-amino-4-(5-imidazolyl)butanoic acid, 2-amino-3-(1-imidazolyl)propanoic acid, 2-amino-3-(2-imidazolyl)propanoic acid, 2-amino-(1-pyrazolyl)propanoic acid, 2-amino-(3-pyrazolyl)propanoic acid, 2-amino-(3,5-dialkyl-4-pyrazolyl)propanoic acid, 2-amino-3-(3-amino-1,2,4-triazol-1-yl)propanoic acid, 2-amino-3-(tetrazol-5-yl)propanoic acid, 2-amino-4-(5-tetrazolyl)butanoic acid, 2-amino-3-(6-methyl-3-indolyl)propanoic acid, 2-amino-3-(4-fluoro-3-indolyl)propanoic acid, 2-amino-3-(5-fluoro-3-indolyl)propanoic acid, 2-amino-3-(6-fluoro-3-indolyl)propanoic acid, 2-amino-3-(4,5,6,7-tetrafluoro-3-indolyl)propanoic acid, 2-amino-3-(5-chloro-3-indolyl)propanoic acid, 2-amino-3-(6-chloro-3-indolyl)propanoic acid, 2-amino-3-(7-chloro-3-indolyl)propanoic acid, 2-amino-3-(5-bromo-3-indolyl)propanoic acid, 2-amino-3-(7-bromo-3-indolyl)propanoic acid, 2-amino-3-(2-hydroxy-3-indolyl)propanoic acid, 2-amino-3-(5-hydroxy-3-indolyl)propanoic acid, 2-amino-3-(7-hydroxy-3-indolyl)propanoic acid, 2-amino-3-(2-alkylmercapto-3 -indolyl)propanoic acid, 2-amino-3-(7-amino-3-indolyl)propanoic acid, 2-amino-3-(4-nitro-3-indolyl)propanoic acid, 2-amino-3-(7-nitro-3-indolyl)propanoic acid, 2-amino-3-(4-carboxy-3-indolyl)propanoic acid, 2-amino-3-(3-indolyl)butanoic acid, 2-amino-3-(2,3-dihydro-3-indolyl)propanoic acid, 2-amino-3-(2,3-dihydro-2-oxo-3-indolyl)propanoic acid, 2-amino-3-alkylmercapto-3-(3-indolyl)propanoic acid, 2-amino-3-(4-aza-3-indolyl)propanoic acid, 2-amino-3-(7-aza-3-indolyl)propanoic acid, 2-amino-3-(7-aza-6-chloro-4-methyl-3-indolyl)propanoic acid, 2-amino-3-(2,3-dihydrobenzofuran-3-yl)propanoic acid, 2-amino-3-(3-methyl-5-7-dialkylbenzofuran-2-yl)propanoic acid, 2-amino-3-(benzothiophen-3-yl)propanoic acid, 2-amino-3-(5-hydroxybenzothiophen-3-yl)propanoic acid, 2-amino-3-eoenzoselenol-3yl)propanoic acid, 2-amino-3-quinolylpropanoic acid, 2-amino-3-(8-hydroxy-5-quinolyl)propanoic acid, 2-amino-2-(5,6,7,8-tetrahydroquinol-5-yl)acetic acid, 2-amino-3-(3-coumarinyl)propanoic acid, 2-amino-2-(benzisoxazol-3-yl)acetic acid, 2-amino-2-(5-methylbenzisoxazol-3-yl)acetic acid, 2-amino-2-(6-methylbenzisoxazol-3-yl)acetic acid, 2-amino-2-(7-methylbenzisoxazol-3-yl)acetic acid, 2-amino-2-(5-bromobenzisoxazol-3-yl)acetic acid, 2-amino-3-(benzimidazol-2-yl)propanoic acid, 2-amino-3-(5,6-dichlorobenzimidazol-2-yl)propanoic acid, 2-amino-3-(5,6-dimethylbenzimidazol-2-yl)propanoic acid, 2-amino-3-(4,5,6,7-hydrobenzirnidazol-2-yl)propanoic acid, 2-amino-2-(benzimidazol-5-yl)acetic acid, 2-amino-2-(1,3-dihydro-2,2-dioxoisobenzothiophen-5-yl)acetic acid, 2-amino-2-(1,3-dihydro-2,2-dioxo-2,1,3-benzothiadiazol-5-yl)acetic acid, 2-amino-2-(2-oxobenzimidazol-5-yl)acetic acid, 2-amino-3-(4-hydroxybenzothiazol-6-yl)propanoic acid, 2-amino-3-(benzoxazol-2-yl)propanoic acid, 2-amino-3-(benzothiazol-2-yl)propanoic acid, 2-amino-3-(9-adeninyl)propanoic acid, 2-amino-2-(6-chloro-9-purinyl)acetic acid, 2-amino-2-(6-amino-9-purinyl)acetic acid, 2-amino-3-(6-purinyl)propanoic acid, 2-amino-3-(8-theobrominyl)propanoic acid, 2-amino-2-(1-uracilyl)acetic acid, 2-amino-2-(1-cytosinyl)acetic acid, 2-amino-3-(1-uracilyl)propanoic acid, 2-amino-3-(1-cytosinyl)propanoic acid, 2-amino-4-(1-pyrimidinyl)butanoic acid, 2-amino-4-(4-amino-1-pyrimidinyl)butanoic acid, 2-amino-4-(4-hydroxy-1-pyrimidinyl)butanoic acid, 2-amino-5-pyrimidinyl)pentanoic acid, 2-amino-5-(4-hydroxy-1-pyrimidinyl)pentanoic acid, 2-amino-3-(5-pyrimidinyl)propanoic acid, 2-amino-3-(6-uracilyl)propanoic acid, 2-amino-3-(2-pyrimidinyl)propanoic acid, 2-amino-3-(6-amino-4-chloro-2-pyrimidinyl)propanoic acid, 2-amino-3-(4-hydroxy-2-pyrimidinyl)propanoic acid, 2-amino-3-(2-amino-4-pyrimidinyl)propanoic acid, 2-amino-3-(4,5-dihydroxypyrimidin-2-yl)propanoic acid, 2-amino-3-(2-thiouracil-6-yl)propanoic acid, 2-amino-2-(5-alkyl-2-tetrahydrofuryl)acetic acid, 2-amino-2-(5-methyl-2,5-dihydro-2-furyl)acetic acid, 2-amino-2-(5-alkyl-2-furyl)acetic acid, 2-amino-2-(2-furyl)acetic acid, 2-amino-2-(3-hydroxy-5-methyl-4-isoxazolyl)acetic acid, 2-amino-3-(4-bromo-3-hydroxy-5-isoxazolyl)propanoic acid, 2-amino-3-(4-methyl-3-hydroxy-5-isoxazolyl)propanoic acid, 2-amino-3-(3-hydroxy-5-isoxazolyl)propanoic acid, 2-amino-2-(3-chloro-D2-isoxazolin-5-yl)acetic acid, 2-amino-2-(3-oxo-5-isoxazolidinyl)acetic acid, 2-amino-3-(3,5-dioxo-1,2,4-oxadiazolin-2-yl)propanoic acid, 2-amino-3-(3-phenyl-5-isoxazolyl)propanoic acid, 2-amino-3-[3-(4-hydroxyphenyl)-1,2,4-oxadiazol-5-yl]propanoic acid, 2-amino-3-(2-thienyl)propanoic acid, 2-amino-2-(2-furyl)acetic acid, 2-amino-2-(2-thienyl)acetic acid, 2-amino-2-(2-thiazolyl)acetic acid, 2-amino-3-(2-thiazolyl)propanoic acid, 2-amino-4-(4-carboxy-2-thiazolyl)butanoic acid, 2-amino-3-(4-thiazolyl)propanoic acid, 2-amino-3-(2-selenolyl)propanoic acid, 2-amino-3-(2-amino-4-selenolyl)propanoic acid, and 2-amino-3-(beta-ribofuranosyl)propanoic acid.
xe2x80x9cAmino acids residuexe2x80x9d also refers to various amino acids where sidechain functional groups are coupled with appropriate protecting groups known to those skilled in the art. xe2x80x9cThe Peptidesxe2x80x9d, Vol 3, 3-88 (1981) discloses numerous suitable protecting groups and is incorporated herein by reference for that purpose. Examples of amino acids where sidechain functional groups are coupled with appropriate protecting groups include, but are not limited to, Asp(OMe), Glu(OMe), Hyp(OMe), Asp(OtBu), Glu(OtBu), Hyp(OtBu), Thr(OtBu), Asp(OBzl), Glu(OBzl), Hyp(OBzl), and Thr(OBzl).
The phrase xe2x80x9cpharmaceutically acceptablexe2x80x9d is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
As used herein, xe2x80x9cpharmaceutically acceptable saltsxe2x80x9d refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic groups such as amines; and alkali or organic salts of acidic groups such as carboxylic acids. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, and nitric; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, and isethionic.
The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington""s Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418, the disclosure of which is hereby incorporated by reference.
Since prodrugs are known to enhance numerous desirable qualities of pharmaceuticals (e.g., solubility, bioavailability, manufacturing, etc.) the compounds of the present invention may be delivered in prodrug form. Thus, the present invention is intended to cover prodrugs of the presently claimed compounds, methods of delivering the same and compositions containing the same. xe2x80x9cProdrugsxe2x80x9d are intended to include any covalently bonded carriers which release an active parent drug of the present invention in vivo when such prodrug is administered to a mammalian subject. Prodrugs of the present invention are prepared by modifying functional groups present in the compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compound. Prodrugs include compounds of the present invention wherein a hydroxy, amino, or sulfhydryl group is bonded to any group that, when the prodrug of the present invention is administered to a mammalian subject, it cleaves to form a free hydroxyl, free amino, or free sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol and amine functional groups in the compounds of the present invention.
xe2x80x9cStable compoundxe2x80x9d and xe2x80x9cstable structurexe2x80x9d are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
xe2x80x9cTherapeutically effective amountxe2x80x9d is intended to include an amount of a compound of the present invention or an amount of the combination of compounds claimed effective to inhibit HCV infection or treat the symptoms of HCV infection in a host. The combination of compounds is preferably a synergistic combination. Synergy, as described for example by Chou and Talalay, Adv. Enzyme Regul. 1984, 22, 27-55, occurs when the effect (in this case, inhibition of the desired target) of the compounds when administered in combination is greater than the additive effect of the compounds when administered alone as a single agent. In general, a synergistic effect is most clearly demonstrated at suboptimal concentrations of the compounds. Synergy can be in terms of lower cytotoxicity, increased antiviral effect, or some other beneficial effect of the combination compared with the individual components.
The compounds of the present invention can be prepared in a number of ways well known to one skilled in the art of organic synthesis. The compounds of the present invention can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereon as appreciated by those skilled in the art. Preferred methods include, but are not limited to, those described below. All references cited herein are hereby incorporated in their entirety herein by reference.
The novel compounds of this invention may be prepared using the reactions and techniques described in this section. The reactions are performed in solvents appropriate to the reagents and materials employed and are suitable for the transformations being effected. Also, in the description of the synthetic methods described below, it is to be understood that all proposed reaction conditions, including choice of solvent, reaction atmosphere, reaction temperature, duration of the experiment and workup procedures, are chosen to be the conditions standard for that reaction, which should be readily recognized by one skilled in the art. It is understood by one skilled in the art of organic synthesis that the functionality present on various portions of the molecule must be compatible with the reagents and reactions proposed. Such restrictions to the substituents which are compatible with the reaction conditions will be readily apparent to one skilled in the art and alternate methods must then be used.
The compounds of this invention are intended to interact with the catalytic serine hydroxyl of Hepatitis C NS3 protease, and therefore incorporate an electrophilic moiety capable of such interaction. In the synthetic schemes below, this moiety, or its synthetic equivalent or precursor, is referred to as a xe2x80x9cserine trapxe2x80x9d and is defined by structure 1-10.
Synthesis of inhibitors 1-11, 1-12, and 1-13
Scheme 1 illustrates the synthesis of inhibitors of structure 1-11, 1-12 and 1-13. In Scheme 1, R3, A3, R8, R1,and W are as defined above; R1xe2x80x3, is H or small alkyl group, for example methyl or ethyl, P is a nitrogen protecting group, and R is a standard leaving group for carboxylic acids, wherein such protecting and leaving groups are known to one skilled in the art.
a) Protected cyclic amine (n=1-3) is oxidized with rutnenium oxide in a two-phase system (Yoshifuji, S. et al, Chem. Pharma. Bull. 1986, 34, 3873-3878) to the corresponding lactam 1-1 (n=1-3), then treated with strong base and alkylated with electrophile. It can be monoalkylated or dialkylated with R3-Xxe2x80x3 and R13-Xxe2x80x3 to give 4-substituted pyroglutamate 1-2. Pyroglutamate 1-2 is reduced by diisobutylaluminum hydride (DIBAL) or lithium triethylborohydride (super hydride) to the corresponding aminal 1-3, which is exchanged with methanol under acidic condition through acyl-iminium ion chemistry to 5-methoxyl-1-tert-butoxycarbonylpyroglutamate 1-4. Synthesis of compound 1-4 may also be accomplished using the chemistry outlined in Scheme 2. Briefly, N-protected glutamic acid derivative 2-4a is converted to thioester 2-4b catalyzed by EDC/DMAP. The thioester 2-4b is reduced to aldehyde by triethylsilane (Fukuyama, T. et al. J. Am. Chem. Soc. 1990, 112, 7050-7051), which reacts in an intramolecular fashion to give compound 1-4 in methanol.
b) 5-Methoxy pyroglutamate 1-4 is reacted with trimethylsilyl cyanide catalyzed by a Lewis acid such as ZnCl2 or BF3 etherate in methylene chloride to give 5-cyano pyroglutamate 1-5. The protecting group is removed to generate aminonitrile salt 1-6. The salt is reacted with oxalyl chloride or bromide at elevated temperature to produce dihydropyrrolopyrazinone 1-7 wherein R6 is Cl or Br. 
c) Dihydropyrrolopyrazinone 1-7 reacts with amine A3R8NH2 regiospecifically to give 3-amino-dihydropyrrolopyrazinone 1-8 in ethyl acetate or dioxane. When A3xe2x95x90R8xe2x95x90H, the amino group can be coupled to a suitably protected peptide fragment by methods known to one skilled in the art. The remaining chlorine or bromine is then optionally removed by hydrogenolysis or can be coupled to organometalic reagents using the chemistry known as Heck and Suzuki coupling (Suzuki et al. Chem. Rev. 1995, 95, 2457-2483). Hydrolysis of the ester 1-8 to the free acid, and peptide coupling with a serine trap H2NC(R1R1xe2x80x3)W (1-10) affords the inhibitor 1-11. Similarly, an inhibitor of formula 1-12 or 1-13 can be made from precursor 1-1a following the analogous chemistry describe above. 1-1a is made according to the chemistry described by Sardina et al (Blanco, M. et al, J. Org. Chem. 1999, 64, 8786-8793).
Compound 1-11, 1-12 or 1-13 are further purified by techniques known to those skilled in the art. These include silica gel chromatography, reverse phase HPLC, and size exclusion chromatography using Sephedex(trademark) LH-20.
Synthesis of a serine trap of structure 1-10
a) Synthesis of xe2x80xa2-amino boronic ester
Scheme 3 outlines a route to mono-substituted amino boronic esters. In Scheme 3, a Grignard reagent is reacted with a borate ester 3-12a, which can be prepared by the reaction of pinanediol with trialkylborate, providing boronate 3-12b. Homologation of 3-12b with the anion of dichloromethane gives the xe2x80xa2-chloro boronic ester 3-12c. (Matteson, D. S.; Majumdar, D. Organometallics 1983, 2, 1529-1535). Displacement of the chloride by lithium bis(trimethylsilyl)amide gives silyl amine 3-12d, which is converted to the amine hydrochloride salt 3-12e with anhydrous HCl. (Matteson, D. S. Sadhu, K. M. Organometallics 1984, 3, 1284-1288). Notice that 3-12e is shown protected as the pinanediol ester. This is the preferred protecting group, but other diol protecting groups, for example but not to be limiting the scope of workable and known diol protecting groups, pinacol, 1,2-ethanediol, 1,2-propanediol, 1,3-propanediol, 2,3-butanediol, 1,2-diisopropylethanediol, 5,6-decanediol, 1,2-dicyclohexylethanediol, are known to those skilled in the art.
Peptide boronic esters can be prepared from commercially available materials by methods known to one skilled in the art of organic synthesis. Peptide boronic acids and esters are generally well known in the art; however, for a general reference to synthesis of peptide boronic esters, see: Kettner, C; Forsyth, T. Houben-Weyl Methods of Organic Chemistry 1999, in press; for a reference to synthesis of fluorinated peptide residues see Matassa, V. et al., PCT Application WO 9964442, published Dec. 12, 1999. More preferably, see techniques disclosed in copending commonly assigned U.S. Provisional Patent Application 60/142,561, filed Jul. 7, 1999; herein incorporated in its entirety by reference; as well as copending commonly assigned U.S. Provisional Patent Application Ser. No. 60/145,631, filed Jul. 26, 1999; herein incorporated in its entirety by reference. 
b) Synthesis of xcex1-ketoamide, xcex1-ketoester and xcex1-diketone
xcex1-Ketoamides and other xcex1-keto derivatives are generally introduced in the hydroxy form and oxidized to the active ketone form in the final synthetic step after it is coupled to the pyrazinone carboxylic acid 1-9. Scheme 4 illustrates the synthesis of xcex1-hydroxy esters and xcex1-hydroxy amides. In Scheme 4, substituted acrylate ester 4-13a is aminohydroxylated using a Sharpless""s procedure (Tao, B., Sharpless, K. B. et al. Tetrahedron Lett. 1998, 39, 2507-2510) to Cbz-protected amino alchol 4-13b. Catalytic hydrogenation of 4-13b gives a-hydroxy ketoester 4-13c. Alternatively, 4-13b is hydrolyzed to free acid 4-13d and coupled to amine H2N-Q to give Cbz-protected amino xcex1-hydroxy amide 4-13e. Catalytic hydrogenation of 4-13e gives xcex1-hydroxy ketoamide 4-13f. For other methods to prepare xcex1-keto esters, amides or other electrophilic carbonyl derivatives, see: N. P. et al. Tetrahedron Lett. Peet, 1988, 3433-3436; Edwards, P. D.; Bernstein, P. R. Medicinal Res. Reviews 1994, 14, 127-194, and references cited therein; Sharpless, K. B.; et al, Angew. Chem. Int. Ed. Engl. 1996, 35, 451; and Sharpless, K. B. et al, Angew. Chem. Int. Ed. Engl. 1996, 35, 2813. Many of the xcex1, xcex2-unsaturated esters, 4-13a, are commercially available or may be easily prepared from commercially available materials.
Amines of formula H2N-Q can be prepared from commercially available materials by methods known to one skilled in the art of organic synthesis. More preferably, see techniques disclosed in copending commonly assigned U.S. Provisional Patent Application Ser. No. 60/168,998, filed Dec. 3, 1999; herein incorporated in its entirety by reference. 
c) Synthesis of amino trifluoromethyl and pentafluoroethyl ketones.
Similar toa-ketoamides and other a-keto derivatives, the trifluoromethyl or pentafluoroethyl ketone functionality is also introduced in the hydroxy form and oxidized to the active ketone form in the final step. Scheme 5 illustrates the synthesis of amino trifluoromethyl alcohol (Skiles, J. W. et al. J. Med. Chem. 1992, 35, 641-662) and amino pentafluoroethyl alcohol (Ogilvie, W. et al. J. Med. Chem. 1997, 40, 4113-4135). In Scheme 5, a Henry reaction between a nitroalkane R1NO2 and trifluoroacetaldehyde ethyl hemiacetal affords nitro alcohol 5-14a, which is hydrogenated over Ra-Ni and the resulting amino alcohol 5-14b is converted to the N-Boc derivative 5-14c. Treatment of the Boc-amine with anhydrous HCl affords the hydrochloride salt 5-14d. A solid-phase synthesis of peptidyl trifluoromethyl ketones is also known, see: Poupart, M.-A., et al. J. Org. Chem. 1999, 64, 1356-1361. Alternatively, condensation of the Weinreb amide 5-15a with CF3CF2Li followed by reduction with NaBH4 gives pentafluoroethyl substituted alcohol 5-15b. Deprotection of 5-15b gives the amino alcohol salt 5-15d. 
d) Synthesis of difluoro xcex2-ketoamide
Scheme 6 outlines the synthesis of hydroxy difluoro xcex2-ketoamides (see: Veale, C. A. et al. J. Med. Chem. 1997, 40, 3173-3181; Wolfe, M. S. et al. J. Med. Chem. 1998, 41, 6-9). In Scheme 6, protected aminoaldehyde 6-16a (For preparation of xcex1-aminoaldehyde, see: Fukuyama, T. et al. J. Am. Chem. Soc. 1990, 112, 7050-7051 and Scheidt, K. A. et al. Bioorg. Med. Chem. 1998, 6, 2477-2499) is reacted with 2-bromo-2,2-difluoroacetate to produce difluoro alcohol 6-16b. The alcohol 6-16b is hydrolyzed to the acid and coupled to an amine H2N-Q to give 6-16c. The nitrogen protecting group Pg is removed according to procedures known to one skilled in the art (see Greene, T. W. in Protective Groups in Organic Synthesis, John Wiley and Sons, 2nd Ed, 1991), producing difluoro xcex2-ketoamide 6-16d. 
The serine traps described above are generally coupled to the free acid of the dihydropyrrolopyrazinone using known peptide coupling procedures, preferably by the phosphonium salt PyAOP (Carpino, et al. J. Chem. Soc., Chem. Commun. 1994, 201-203). The alcohol functionality of the hydroxy serine trap is oxidized by procedures known to those skilled in the art, such as Dess-Martin periodinane method (Dess, D. B, Martin, J. C. J. Org. Chem. 1983, 48, 4155-4156) in the final step to give a compound of structure 1-11 and 1-12
wherein W contains an activated carbonyl.
When required, separation of the racemic material can be achieved by HPLC using a chiral column or by a resolution using a resolving agent such as camphonic chloride (Steven D. Young, et al, Antimicrobial Agents and Chemotheraphy 1995, 2602-2605). A chiral compound may also be directly synthesized using a chiral catalyst or a chiral ligand (Andrew S. Thompson, et al, Tet. lett. 1995, 36, 8937-8940).
Other features of the invention will become apparent in the course of the following descriptions of exemplary embodiments which are given for illustration of the invention and are not intended to be limiting thereof.